Archive for the ‘reaction mechanism’ Category

Unexpected Isomerization of Oxetane-Carboxylic Acids – an alternative autocatalytic mechanism evaluated.

Wednesday, August 17th, 2022

Previously, I looked at autocatalytic mechanisms where the carboxyl group of an oxetane-carboxylic acid could catalyse its transformation to a lactone, finding that a chain of two such groups were required to achieve the result. Here I look at an alternative mode where the oxetane-carboxylate itself acts as the transfer chain, via a H-bonded dimer shown below.

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Unexpected Isomerization of Oxetane-Carboxylic Acids – substrate design.

Sunday, August 14th, 2022

Having established a viable model for the unexpected isomerism of oxetane carboxylic acids to lactones[1], and taken a look at a variation in the proton transfer catalyst needed to accomplish the transformation, I now investigate the substrate itself.

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References

  1. B. Chalyk, A. Grynyova, K. Filimonova, T.V. Rudenko, D. Dibchak, and P.K. Mykhailiuk, "Unexpected Isomerization of Oxetane-Carboxylic Acids", Organic Letters, vol. 24, pp. 4722-4728, 2022. http://dx.doi.org/10.1021/acs.orglett.2c01402

Unexpected Isomerization of Oxetane-Carboxylic Acids – catalyst design.

Saturday, 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.

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

Sunday, August 7th, 2022

Derek Lowe’s blog has a recent post entitled A Downside to Oxetane Acids which picks up on a recent article[1] 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.

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References

  1. B. Chalyk, A. Grynyova, K. Filimonova, T.V. Rudenko, D. Dibchak, and P.K. Mykhailiuk, "Unexpected Isomerization of Oxetane-Carboxylic Acids", Organic Letters, vol. 24, pp. 4722-4728, 2022. http://dx.doi.org/10.1021/acs.orglett.2c01402

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

Wednesday, 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.[1]

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References

  1. H. Staudinger, "Oxalylchlorid", Berichte der deutschen chemischen Gesellschaft, vol. 41, pp. 3558-3566, 1908. http://dx.doi.org/10.1002/cber.19080410335

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

Saturday, June 11th, 2022

Minds (and memories) can work in wonderful ways. In 1987[1] 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).

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References

  1. A.M. Lobo, M.M. Marques, S. Prabhakar, and H.S. Rzepa, "Tetrahedral intermediates formed by nitrogen and oxygen attack of aromatic hydroxylamines on acetyl cyanide", The Journal of Organic Chemistry, vol. 52, pp. 2925-2927, 1987. http://dx.doi.org/10.1021/jo00389a050

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

Monday, 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)[1], 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[2] is shown below:

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References

  1. T. Steiner, I. Majerz, and C.C. Wilson, "First O−H−N Hydrogen Bond with a Centered Proton Obtained by Thermally Induced Proton Migration", Angewandte Chemie International Edition, vol. 40, pp. 2651-2654, 2001. http://dx.doi.org/10.1002/1521-3773(20010716)40:14<2651::AID-ANIE2651>3.0.CO;2-2
  2. I. Majerz, and M.J. Gutmann, "Mechanism of proton transfer in the strong OHN intermolecular hydrogen bond", RSC Advances, vol. 1, pp. 219, 2011. http://dx.doi.org/10.1039/C1RA00219H

Dimerisation of cyclopropenylidene: what are the correct “curly arrows” for this process?

Wednesday, July 21st, 2021

In another post, a discussion arose about whether it might be possible to trap cyclopropenylidene to form a small molecule with a large dipole moment. Doing so assumes that cyclopropenylidene has a sufficiently long lifetime to so react, before it does so with itself to e.g. dimerise. That dimerisation has an energy profile shown below, with a free energy of activation of 14.4 kcal/mol, so a facile reaction that will indeed compete with reaction with Ph-I+-CC.

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Dimethyl ketal hydrolysis catalysed by hydroxide and hydronium ions

Wednesday, April 7th, 2021

In the preceding post, I looked at a computed mechanism for the hydrolysis of a ketal by water. Of course, pure water consists of three potential catalysts, water itself or [H2O], and the products of autoionisation, [OH] and [H3O+]. The latter are in much smaller concentration, equivalent to a penalty of ~11.9 kcal/mol on any free energy barrier. Here I take a look at these ion-catalysed routes to see if that penalty can be overcome.

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A computational mechanism for the aqueous hydrolysis of a ketal to a ketone and alcohol.

Thursday, April 1st, 2021

The previous post was about an insecticide and made a point that the persistence of both insecticides and herbicides is an important aspect of their environmental properties. Water hydrolysis will degrade them, a typical residency time being in the order of a few days. I noted in passing a dioxepin-based herbicide[1] which contains a ketal motif and which in water can hydrolise to a ketone and alcohol. The reverse (acid catalysed) formation of a ketal is a staple of the taught organic chemistry curriculum. Here as a prelude to looking at the hydrolysis of that dioxepin, I take a look at a possible computational mechanism for the hydrolysis of 2,2-dimethoxypropane using pure water, without the help of acid or base.

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References

  1. P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, "Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives", J. Chem. Soc., Perkin Trans. 2, pp. 1265-1269, 1989. http://dx.doi.org/10.1039/P29890001265