Unexpected Isomerization of Oxetane-Carboxylic Acids – substrate design.

August 14th, 2022

Having established a viable model for the unexpected isomerism of oxetane carboxylic acids to lactones[cite]10.1021/acs.orglett.2c01402[/cite], and taken a look at a variation in the proton transfer catalyst needed to accomplish the transformation, I now investigate the substrate itself.

Read the rest of this entry »

Unexpected Isomerization of Oxetane-Carboxylic Acids – catalyst design.

August 13th, 2022

Previously, a mechanism with a reasonable predicted energy was modelled for the isomerisation of an oxetane carboxylic acid to a lactone by using two further molecules of acid to transfer the proton and in the process encouraging an Sn2 reaction with inversion to open the oxetane ring.

Read the rest of this entry »

Web page decay and Journals: How an interactive “ESI” from 2006 was rescued.

August 12th, 2022

In 2006[cite]10.1021/ic0519988[/cite] we published an article illustrating various types of pseudorotations in small molecules. It’s been cited 20 times since then, so reasonable interest! We described rotations known as Lever and Turnstile as well as the better known Berry mode. Because the differences between these rotations are quite subtle, we included an interactive electronic supporting information to illustrate them. That ESI was written in HTML and used Jmol to animate the rotations. Now, 16 years is a long time in the Web ecosystem (some early wag suggested, like dogs, that one year in normal time approximates to about 7 years in Web time) and inevitably, like e.g. both Rasmol[cite]10.1039/P29950000007[/cite] and Chime before it, Jmol no longer works when invoked from a Web browser; Java applets are very much dead and we are now on the fourth generation of molecule viewer, JSmol. Two days ago I was contacted by someone (thanks Peter!) who had noticed that the journal landing page did not seem to point to any ESI. Here I tell the story of what happened next.

Read the rest of this entry »

Unexpected Isomerization of Oxetane-Carboxylic Acids – a viable mechanism

August 12th, 2022

In the previous post, I looked at the intramolecular rearrangement of the oxetane carboxylic acid to a lactone, finding the barrier to the Sn2 reaction with retention was unfeasibly high. Here I explore alternatives.

Read the rest of this entry »

Unexpected Isomerization of Oxetane-Carboxylic Acids – a first look at the mechanism

August 7th, 2022

Derek Lowe’s blog has a recent post entitled A Downside to Oxetane Acids which picks up on a recent article[cite]10.1021/acs.orglett.2c01402[/cite] describing how these acids are unexpectedly unstable, isomerising to a lactone at a significant rate without the apparent need for any catalyst. This is important because these types of compound occur frequently in the medicinal chemistry literature.

Read the rest of this entry »

Personal Impressions from WATOC 2020 – Dispersion and non Born-Oppenheimer models.

July 11th, 2022

WATOC 2020 was just held in 2022 in Vancouver Canada, over one week. With many lectures held in parallel, it is not possible for one person to cover anything like the topics presented, so this is a personal view of some of those talks that I attended. As happens with many such events, common themes gradually emerge and here I highlight just two that struck me as important for the future of computational chemistry.

Read the rest of this entry »

Dioxane tetraketone – an ACS molecule of the week with a mystery.

June 22nd, 2022

I have long been fascinated by polymers of either carbon dioxide, or carbon monoxide, or combinations of both. One such molecule, referred to as dioxane tetraketone when it was featured on the ACS molecule-of-the-week site and also known as the anhydride of oxalic acid, or more formally 1,4-dioxane-2,3,5,6-tetraone, has been speculated upon for more than a century.[cite]10.1002/cber.19080410335[/cite]

Read the rest of this entry »

Checking a conclusion we made in 1987: Tetrahedral intermediates formed by nitrogen and oxygen attack of aromatic hydroxylamines on acetyl cyanide

June 11th, 2022

Minds (and memories) can work in wonderful ways. In 1987[cite]10.1021/jo00389a050[/cite] we were looking at the properties of “stable” tetrahedral intermediates formed in carbonyl group reactions. The reaction involved adding phenylhydroxylamine to acetyl cyanide. NMR signals for two new species were detected, and we surmised one was due to N-attack on the carbonyl and one was due to O-attack, in each case to form a stable tetrahedral intermediate. To try to identify which was which, 15N labelled hydroxylamine was used and then the 15N-13C coupling constants were measured, which could either be 1-bondJ (for N-attack) or 2-bondJ (for O-attack).

Read the rest of this entry »

3-Methyl-5-phenylpyrazole: a crystallographic enigma?

May 19th, 2022

Previously, I explored the unusual structure of a molecule with a hydrogen bonded interaction between a phenol and a pyridine. The crystal structure name was RAKQOJ and it had been reported as having almost symmetrical N…H…O hydrogen bonds. This feature had been determined using neutron diffraction crystallography, which is thought very reliable at determining proton positions. Another compound with these characteristics is 3-methyl-5-phenylpyrazole or MEPHPY01.[cite]10.1039/p29750001068[/cite] Here the neutron study showed it to apparently have the structure represented below, where the solid N-H lines indicate a proton equidistant between two nitrogens.

Read the rest of this entry »

Geometries of proton transfers: modelled using total energy or free energy?

April 18th, 2022

Proton transfers are amongst the most common of all chemical reactions. They are often thought of as “trivial” and even may not feature in many mechanistic schemes, other than perhaps the notation “PT”. The types with the lowest energy barriers for transfer often involve heteroatoms such as N and O, and the conventional transition state might be supposed to be when the proton is located at about the half way distance between the two heteroatoms. This should be the energy high point between the two positions for the proton. But what if a crystal structure is determined with the proton in exactly this position? Well, the first hypothesis is that using X-rays as the diffracting radiation is unreliable, because protons scatter x-rays very poorly. Then a more arduous neutron diffraction study is sometimes undertaken, which is generally assumed to be more reliable in determining the position of the proton. Just such a study was undertaken for the structure shown below (RAKQOJ)[cite]10/c3zxh2[/cite], dataDOI: 10.5517/cc57db3 for the 80K determination. The substituents had been selected to try to maximise the symmetry of the O…H…N motif via pKa tuning (for another tuning attempt, see this blog). The more general landscape this molecule fits into[cite]10.1039/C1RA00219H[/cite] is shown below:

Read the rest of this entry »