The secrets of FAIR Metadata: optimisation for Chemical Compounds.

December 11th, 2024

The idea of so-called FAIR (Findable, Accessible, Interoperable and Reusable) data is that each object has an associated metadata record which serves to enable the four aspects of FAIR. Each such record is itself identified by a persistent identifier known as a DOI. The trick in producing useful FAIR data is defining what might be termed the “granularity” of data objects that generate the most readily findable and which most usefully enable the other three attributes of FAIR.

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Data Discovery: A pick-n-mix library of useful FAIR Data searches – and a call for new search suggestions.

November 25th, 2024

With AI and Machine learning needing data in abundance, interest in data discovery is intense. However, this type of discovery is somewhat different from more traditional data base searches, in that it is particularly suited for machine discovery as well as by humans. The discovery searches are conducted using an aggregated and federated metadata store, such as that curated by DataCite. How to construct a suitable search is however still not entirely human-friendly. The start point for understanding how to search is this resource: XML to JSON mappings and the XML referred to can be found here. [cite]10.14454/g8e5-6293[/cite] Since the learning curve to construct such data searches can be quite steep, I thought I would share as a library some recent searches I constructed for a talk I am giving. This post is essentially an extension and update of an earlier challenge I was set along these lines and which appeared here.[cite]10.1255/sew.2022.a10[/cite]

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Mechanism of the Masamune-Bergman reaction. Part 4. Why was the DFT energy barrier too high for the Calicheamicin reaction?

October 29th, 2024

Michael in a comment here on the mechanism of the Masamune-Bergman reaction notes that when it occurs as part of the Calicheamicin (an antibody-drug conjugate or ADC) version of this mechanism, a pre-step is first necessary. As discussed in this review article,[cite]10.3390/ph14050442[/cite] the trisulfide linkage is reduced and the resulting thiolate undergoes a facile 1,4-addition to the adjacent enone.

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A one-electron bond in methyl-λ1-borane.

October 9th, 2024

In exploring one-electron carbon-carbon bonds, I had noted previously[cite]10.59350/88k04-2×509[/cite] that both hexafluoroethane and ethane itself could each lose an electron to produce such species. A discussion developed in which a molecule isoelectronic with ethane, namely the methyl-λ1-borane radical (H3B-CH3) was proposed by Jacob. The optimised structure at the ωB97XD/6-31G(d) level exhibited a B-C bond length of 1.57Å, with two of the B-H hydrogens forming a a 3c-3e bond with boron and so a one-electron B-C bond was discounted. Here I take a closer look at this system.

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The one-electron carbon-carbon bond: Hexafluoroethane and ethane radical cations.

October 3rd, 2024

In the previous post, I looked[cite]10.59350/xp5a3-zsa24[/cite] at the recently reported[cite]10.1021/ja02261a002[/cite] hexa-arylethane containing a carbon-carbon one-electron bond, its structure having been determined by x-ray diffraction (XRD). The measured C-C bond length was ~2.9aÅ and my conclusion was that the C…C region represented more of a weak “interaction” than of a bond as such. How about a much simpler system, hexafluoroethane? Here, the two-electron C-F bonds are much lower in energy than the C-C bond, so when the molecule is ionised, it escapes from the C-C bond rather than any of the C-F bonds. The below is the structure computed at the ωB97XD/Def2-TZVPP level, revealing a much shorter C-C bond of 2.149Å. The computed C-C stretching vibrational frequency is 179 cm-1 (FAIR data DOI: [cite]10.14469/hpc/14642[/cite])

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A carbon-carbon one-electron bond! Or a weak carbon-carbon interaction?

October 1st, 2024

More than 100 years ago, before the quantum mechanical treatment of molecules had been formulated, G. N. Lewis proposed[cite]10.1021/ja02261a002[/cite] a simple model for chemical bonding that is still taught today. This is the idea of the three categories of bond we know as single, double and triple, comprising respectively two, four and six shared electrons each, at least for the very common carbon-carbon bond. A little more than a decade ago, this was extended upwards to the eight-electron quadruple bond.[cite]10.1038/nchem.1263[/cite]. Now, at the other extreme of downwards, a molecule has been characterised in the solid state with a one-electron C-C bond.[cite]10.1038/s41586-024-07965-1[/cite] In this sub-two-electron region, bonds such as hydrogen bonds have long been recognised and they form part of a class of “weak” bonding known instead as exhibiting “non-covalent-interactions” or NCI. But specifically a one-electron carbon-carbon bond stands apart from these weaker types and so it is certainly news when one such is reported and characterised in the crystalline state by x-ray diffraction.

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Mechanism of the Masamune-Bergman reaction. Part 3: The transition state for Calicheamicin models.

September 11th, 2024

Calicheamicin was noted in the previous post as a natural product with antitumour properties and having many weird structural features such as  an unusual “enedidyne” motif. The representation is shown below.

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Mechanism of the Masamune-Bergman reaction. Part 2: a possible 3D Model for Calicheamicin revealing the non-covalent-interactions (NCI) present.

August 26th, 2024

Calicheamicin is a natural product with antitumour properties discovered in the 1980s, with the structure shown below. As noted elsewhere, this structure has many weird properties, including amongst other features an unusual “enedidyne” motif and the presence of an iodo group on an aromatic ring. Its isolated 3D structure is quite difficult to get hold of (embedded structures in a DNA fragment are available however); the 3D model associated with the Wikipedia entry is essentially only in 2D. The representation shown below, including the absolute stereochemistry, was obtained from the SciFinder entry.

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Mechanism of the Masamune-Bergman reaction. Part 1.

August 24th, 2024

The Masamune-Bergman reaction[cite]10.1039/C29710001516[/cite],[cite]10.1021/ja00757a071[/cite] is an example of  a highly unusual class of chemical mechanism[cite]10.1021/cr4000682[/cite] involving the presumed formation of the biradical species shown as Int1 below by cyclisation of a cycloenediyne reactant. Such a species is  so reactive that it will be quickly trapped, as for example by dihydrobenzene to form the final product. This cycloenediyne is not just an obscure chemical curiosity, the motif is incorporated into the natural product Calicheamicin, which is a potent antitumor antibiotic discovered in the 1980s. This drug owes its activity to the cyclisation TS1 shown below, which for n=2 occurs at the low temperature of 310K. The resulting biradical Int1 is a potent hydrogen abstractor, the species acting this way for hydrogen atoms associated with deoxyribose of DNA, ultimately leading to strand scission. Although I have explored many a mechanism on this blog using computational methods, I have never included any biradical examples. Here I explore the computational aspects of this reaction, and also include a pathway proceeding vis TS2- Int2 – TS3 in which hydrogen abstraction precedes cyclisation, in order to see how competitive such an alternative might be as a function of the ring size (n in scheme below).

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Revisiting open/transparent peer review.

July 31st, 2024

Back in 2017, I was asked to peer review an article and its author asked if I would like the review to be “open” – that is that my name would be shown as a reviewer; [cite]10.1073/pnas.1709586114[/cite/] indeed it was!

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