The Willgerodt-Kindler Reaction: mechanistic reality check 2.

August 14th, 2020

Continuing an exploration of the mechanism of this reaction, an alternative new mechanism was suggested in 1989 (having been first submitted to the journal ten years earlier!).[1] Here the key intermediate proposed is a thiirenium cation (labelled 8 in the article) and labelled Int3 below.

The model chosen is the same as before (B3LYP+GD3+BJ/Def2-TZVPP/Solvent=water) but now includes a specific base (ammonia) to help remove and add protons. Species 8 (Int3) sits in the middle of the rearrangement mechanism and can account for isomerisation in which (above) the Ph and H substituents of the starting ketone end up transposed. It also has the apparent merit that cations such as 8 are known as crystal structures[2],[3]+ DOI: 10.5517/cc112bct,[3]+DOI: 10.5517/cc112bfw. As you can see from the relative free energies (FAIR data at DOI: 10.14469/hpc/7336) that of Int3 is 50 kcal/mol higher than the reactant, and the  transition state leading to it is even higher. So whereas species such as 8 (Int3) can exist (albeit substituted with sterically hindering groups), they probably play no actual role in the mechanism of this reaction.

The hunt continues for a mechanism for which the computed energies along the reaction path are ≤ 31 kcal/mol at 403K, which would correspond approximately to a half life of ~60 minutes.  

References

  1. M. Carmack, "The willgerodt‐kindler reactions. 7. The mechanisms", Journal of Heterocyclic Chemistry, vol. 26, pp. 1319-1323, 1989. https://doi.org/10.1002/jhet.5570260518
  2. R. Destro, V. Lucchini, G. Modena, and L. Pasquato, "X-ray Structures and Anionotropic Rearrangements of Di-<i>tert</i>-butyl-Substituted Thiiranium and Thiirenium Ions. A Structure−Reactivity Relationship", The Journal of Organic Chemistry, vol. 65, pp. 3367-3370, 2000. https://doi.org/10.1021/jo991731o
  3. H. Poleschner, and K. Seppelt, "XeF<sub>2</sub>/Fluoride Acceptors as Versatile One‐Electron Oxidants", Angewandte Chemie International Edition, vol. 52, pp. 12838-12842, 2013. https://doi.org/10.1002/anie.201307161

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Question for the day – Einstein, special relativity and atomic weights.

July 25th, 2020

Sometimes a (scientific) thought just pops into one’s mind. Most are probably best not shared with anyone, but since its the summer silly season, I thought I might with this one.

Famously, according to Einstein, m  = E/c^^2, the equivalence of energy to mass. Consider a typical exoenergic chemical reaction:

 A → B, ΔG -100 kJ/mol.  

According to the above, the molecule looses 100 kJ ≡ 1.112650056053618e-18 g after transformation from A to  B. Not much, but possibly measurable using today’s very best technology.

Now for the questions that might arise.

  1. What sort of energy applies above?  If its a free energy, then thermal (zero point and entropic vibrational) energy must clearly contribute. Or is it total energy without thermal and entropic contributions? 
  2. Is the mass loss distributed equally amongst all the atoms. In other words, how much mass does any particular atom lose after reaction or is this question meaningless?
  3. Since clearly the atoms must each lose some mass, that must mean that their atomic weight is a function of the energy content of the molecule they are part of.  A molecule with a lot of internal energy (lets say octanitrocubane, which decomposes to carbon dioxide and nitrogen) must have heavier atoms in the form of cubane than as nitrogen gas.
  4. And to recapitulate the question above, how many orders of magnitude away (if any) might we be from being able to measure this? Or, one can repose this question by asking whether one can measure the mass lost by a battery after discharging?

As with most spontaneous questions, the answers are probably all out there somewhere. Just a matter of finding them!

Here is a real-world example. At the large hadron collider at CERN, about 1011 protons are accelerated to almost the speed of light. During this process, they acquire a mass approaching kgs (I do not recollect the exact value). It certainly is a surprisingly large mass! And it is a surprisingly large amount of energy that has to be injected to achieve this. And when the beam is quenched, that mass is very quickly lost (and a lot of heat is generated in the quenching tunnel).

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The Willgerodt-Kindler Reaction: mechanistic reality check 1.

July 21st, 2020

The Willgerodt reaction[1], discovered in 1887 and shown below, represents a transformation with a once famously obscure mechanism. A major step in the elucidation of that mechanism came[2] using the then new technique of 14C radio-labelling, shortly after the atom bomb projects during WWII made 14CO2 readily available to researchers. Here I am going to start the process of applying the far more recent technique of quantitative quantum mechanical modelling to see if some of the proposed mechanisms stand up to its scrutiny.

In the classic experiment, it was shown that if acetophenone labelled on the carbonyl group with 14C was subjected to Willgerodt conditions, almost 100% of the label ended up in the benzylic carbon(red dot).[2] Why was this considered remarkable? Because it was effectively the oxygen of the carbonyl (via the proxy of the N in the intermediate enamine) that appeared to be migrating along the C2 carbon chain, rather than the phenyl group which is a known very effective migrator! The rather harsh conditions of the Willgerodt reaction were replaced in 1923 by the somewhat milder Kindler modification,[3] using morpholine + S8 as the catalyst instead of ammonia + S8. The mechanism below is adapted from a typical source of named organic reactions; the Wikipedia page is a rather more elaborate version of this. In essence these mechanisms suggest that the aziridine species labelled Int2 below is an undetected intermediate accounting for the radio-labelling experiment.

The computational reality check can be undertaken by calculating the relative free energies of the species labelled above, setting that of the reactant to ΔΔG = 0.0. The model used is B3LYP+GD3+BJ/Def2-TZVPP/SCRF=water (FAIR data DOI: 10.14469/hpc/7294). For the reaction to be reasonably fast at 403K, the highest species on this pathway should be no higher than ~30 kcal/mol above the reactant. The calculations reveal that TS3 is around 42.6 kcal/mol above the reactant, with a very flat potential energy surface in the region of the transition state, in which C-N cleavage preceeds 1,2-hydrogen migration.

The value of this barrier height suggests an alarm bell ringing. Protonating the species (via tosic acid) does not help. So we conclude that the mechanism needs  “optimising” to try to find a lower energy pathway to product.

Species ΔΔG
Reactant 0.0
TS1 27.9 (44.4)a
Int1 5.8 (13.0)a
TS2 16.9 (22.4)a
Int2 14.7
TS3 42.6
Product -21.2
Int3 -0.4
aProtonated on S

A hint of how this might be done comes from the energy of the species labelled Int3, which is a thiirane rather than an aziridine intermediate.  Such thiiranes will be explored in part two of this theme. It may also be that explicit base catalysis of TS3 via proton abstraction may be more facile than a direct [1,2] hydrogen shift. Much like organic syntheses, where reaction yields have to be optimised by often long and arduous explorations, so too on occasion do reaction mechanisms!

References

  1. C. Willgerodt, "Ueber die Einwirkung von gelbem Schwefelammonium auf Ketone und Chinone", Berichte der deutschen chemischen Gesellschaft, vol. 20, pp. 2467-2470, 1887. https://doi.org/10.1002/cber.18870200278
  2. W.G. Dauben, J.C. Reid, P.E. Yankwich, and M. Calvin, "The Mechanism of the Willgerodt Reaction<sup>1</sup>", Journal of the American Chemical Society, vol. 72, pp. 121-124, 1950. https://doi.org/10.1021/ja01157a034
  3. K. Kindler, "Studien über den Mechanismus chemischer Reaktionen. Erste Abhandlung. Reduktion von Amiden und Oxydation von Aminen", Justus Liebigs Annalen der Chemie, vol. 431, pp. 187-230, 1923. https://doi.org/10.1002/jlac.19234310111

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Curly arrows in the 21st Century. Proton-coupled electron transfers.

June 10th, 2020

One of the most fascinating and important articles dealing with curly arrows I have seen is that by Klein and Knizia on the topic of C-H bond activations using an iron catalyst.[1] These are so-called high spin systems with unpaired electrons and the mechanism of C-H activation involves both double headed (two electron) and fish-hook (single electron) movement. Here I focus on a specific type of reaction, the concerted proton-coupled-electron transfer or cPCET, as illustrated below. These sorts of reactions happen also to be of considerable biological importance, including e.g. the mechanism of photosynthesis and many other important transformations.

A hydrogen atom comprises a proton and one electron. The question is whether the proton and the electron travel together as a true hydrogen atom when the hydrogen relocates, or do they each take their separate way, as in the PCET reaction shown above. I will discuss the arrows shown briefly first.

  1. The blue arrow originates at an oxygen lone pair, donating two electrons into a O-H bond. 
  2. The hydrogen starts off with two electrons in a C-H bond. In a pure proton transfer, it would lose both these electrons to the carbon (as an acid) and the proton would travel to the oxygen (as the base, which receives the proton). In fact these two C-H electrons go off in different directions.
    • One (shown with a red fish-hook curly arrow) goes to the carbon to form a carbon radical.
    • The other electron (shown with a dashed fish-hook curly arrow) travels to the Iron. The latter starts off in oxidation state +3 with five unpaired electrons in the high spin state (of which only one is shown above) and is reduced by receiving this electron to an oxidation state +2 and four unpaired electrons (again these are not shown above) with the fifth unpaired electron now becoming a carbon-centered radical. 
  3. The formal charges on the atoms change. The oxygen shares its lone electron pair with a hydrogen and so formally looses its exclusive hold on that electron pair and becomes formally positive. The iron receiving an electron becomes less positive/more negative, changing from Fe(III) ≡ 3+ → Fe(II) ≡ 2+. 
  4. In this representation, both the number of unpaired electrons and the charges balance on both sides of the equation, a crucial aspect of using curly arrows. One cannot create charge out of nothing. Similarly one cannot change the number of unpaired electrons on either side of the equation, unless the electronic state itself changes.
  5. Finally, note that the number of lone pairs in this instance also balance.

Now for an actual calculation of the reaction path using quantum mechanics.[1] The actual molecular model used is shown below. The C-H bond comes from a bis(allylic) alkene, whilst the ligands around the Fe include three neutral imidazole units coordinated through N, the methylalanine aminoacid anion is coordinated through one O(-), neutral acetamide is bound through O and hydroxyl anion (-) completing the octahedral coordination. The two ligand anionic charges noted are formally balanced by Fe(2+), and specifying that the whole system itself has a charge of (+) gives us an oxidation state of Fe(3+) with five formal valence electrons (down from 3d6.4s2 for the neutral atom). Only the hydroxyl ligand to Fe is shown above, the other five are hidden. The whole system is “high spin”, which means it has five unpaired electrons, only one of which is shown for the reactant Fe atom in the schematic diagram above. The other four unpaired and unshown electrons on the Fe are common to both reactant and product.

With the proton going in one direction, and an electron elsewhere, one might expect a change in the dipole moment properties. Below you can see the quite abrupt change in these properties in the same region that the electron/proton transfers happen.

The progress of the reaction is shown by a set of specific types of localised orbital (actually called an IBO or intrinsic bond orbital in this instance) as the reaction evolves from the left to the right. You can think of some of these  orbitals, selected on the basis of their changes in energy as the reaction proceeds, as corresponding to the curly arrows for the reaction. It is possible to reduce such orbitals to a point (a locus) by increasing their isosurface threshold and then to chart these locii as the reaction proceeds. This would then correspond to the path of a curly arrow.  

Below is a specific orbital transformation, corresponding to the curly arrow shown at the top here in dashed red.[1] This orbital starts off located along the C-H bond and as the electron transfers, the orbital morphs (abruptly, like the dipole moment properties above) into an d-orbital located on the iron. It vanishes from one region and re-appears in another, a little like the famous cheshire cat.

When I gave my talk to students alluded to in an earlier post, I was keen to get the message over that the veritable concept of curly arrows, which will be 100 years old in 2024, is still an evolving and modern concept and not stuck in any ancient time warp. This mechanism by Klein and Knizia illustrates nicely how true that is. The take home message is that curly arrows really are fit for the 21st century.

References

  1. J.E.M.N. Klein, and G. Knizia, "cPCET versus HAT: A Direct Theoretical Method for Distinguishing X–H Bond‐Activation Mechanisms", Angewandte Chemie International Edition, vol. 57, pp. 11913-11917, 2018. https://doi.org/10.1002/anie.201805511

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Fascinating stereoelectronic control in Metaldehyde and Chloral.

June 9th, 2020

Metaldehyde is an insecticide used to control slugs. When we unsuccessfully tried to get some recently, I discovered it is now deprecated in the UK. So my immediate reaction was to look up its structure to see if that cast any light (below, R=CH3, shown as one stereoisomer).

A X-ray crystal structure exists (DOI: 10.5517/ccdc.csd.cc20n2pg) and reveals it to be the tetramer of acetaldehyde, or (CH3CHO)4. One further structure came to light, another tetramer of trichloromethylacetaldehyde, known as chloral.[1] This latter compound forms a hydrate, hence chloral hydrate. These two compounds, differing only in the methyl group, show very different conformations of the eight-membered rings. As to why this is, makes for a fascinating story.

Click to obtain 3D model

Firstly, the approach I used. I optimised the structure from the crystal data using ωB97XD/Def2-TZVPP, using C4v symmetry in which all four of the methine hydrogens point in the same direction. The resulting four H…H contacts of 2.13Å are on the short side, and are certainly contributing to the stability by dispersion (London) attractions. The C-O distances are 1.399Å. I then did an ELF (Electron localisation function) analysis to identify what are called the monosynaptic basins. Better known as lone pairs! These (along with the disynaptic basins along the C-O bonds) are shown in purple above. I have displayed the torsion or dihedral angles between each of the lone pairs on oxygen and the adjacent C-O bond (150.1 and 42.0°). This now reveals the so-called anomeric effects in the molecule. Basically one of the lone pairs on oxygen has eight sets of 150.1 angles and the other lone pair eight sets of 42.0°. Only the former lone pairs are close to being anti-periplanar to the adjacent C-O bond. In this geometry, this lone pair can donate into the C-Oσ* orbital of the bond. One can quantify the strength of this interaction using NBO (natural bond orbital) analysis, which gives a so-called E(2) perturbation interaction energy of 19.7 kcal/mol, in total eight of them. The other lone pair on each oxygen shows no discernible interaction.

On to Chloral (X = CCl3). This shows an entirely different geometry with Ci symmetry. This has two distinctly different pairs of oxygen atoms, with a pair of 2.36Å H…H contacts and two pairs of C-O distances 1.406 and 1.378Å; 1.406 and 1.380Å. This asymmetry immediately implies chloral will be more reactive towards e.g. hydrolysis, since one of the C-O bonds is already slightly lengthened. There are 16 distinct dihedral values between an oxygen lone pair and either an adjacent C-O or a C-CCl3 bond. The largest has a torsion angle at C-O of 161.2° with an NBO E(2) energy of 20.6 kcal/mol for a C-O interaction; the other torsions are 149.9, 141.1, 127.5, 112.6, 112.0, 111.1, 74.6, 68.2, 54.1, 42.6, 38.7, 32.6, 20.7, 5.7 and 4.1. There is a new anomeric effect to the adjacent C-CCl3 bond of 12.1 kcal/mol, lower for this latter interaction because the angle (113°) is far from the ideal 180°. In this model, all eight oxygen lone pairs play a role in stabilising the molecule, whereas in metaldehyde only four lone pairs do this.

Click to obtain 3D model

One can now transpose the symmetry of each molecule onto the other compound. Metaldehyde in Ci symmetry is +5.5 kcal/mol higher in free energy and chloral in C4v symmetry is +3.9 kcal/mol. The origins of these difference are probably dissipated across the multiple anomeric effects and H…H dispersion attractions.

This technique of locating the centroids of lone pairs using ELF and then correlating the dihedral angle between the lone pair and any adjacent C-X bond (X = electronegative, which makes the C-X bond a good electron acceptor) is very useful in explaining instances of the anomeric effect and comparing them across isomers.

References

  1. D. Hay, and M. Mackay, "The crystal and molecular structure of metachloral, 2(e),4(e),6(e),8(e)-Tetrakis-(trichloromethy1)-1,3,5,7-tetraoxocan", Australian Journal of Chemistry, vol. 33, pp. 2249-2253, 1980. https://doi.org/10.1071/ch9802249

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The first ever curly arrows. Revisited with some crystal structure mining.

May 27th, 2020

With the current global lockdown, and students along with everyone else staying at home, I have noticed some old posts of mine are getting more attention than normal. One of these is an analysis I did in 2012 of Robinson’s original curly arrow illustration. That and the fact that I am about to give a lecture on what I call my autobiographical journey discovering them, to our own students here (remotely of course), has prompted me to revisit my original discussion.

Of the two modern representations of nitrosobenzene, the first corresponds to Robinson’s arrows, being an attempt to show, by resonance, that the molecule is o/p directing towards an electrophile. Hence the accumulation of negative charge in the p-position (and other resonance structures can be drawn with it in the o-positions) encouraging electrophilic attack there. The second is the modern version, with the electron flow going in the other direction and hence discouraging electrophilic attack at the o/p positions. All this hinges on the observation that the nitrogen lone pair, involved in the first representation, lies in the plane of the molecule and hence is orthogonal (at 90°) to the π-electrons in the benzene ring and cannot overlap with them. In the modern view, this lone pair plays no part in the resonance. 

This can be tested by searching for experimental crystal structures of nitrosobenzenes. I did mention this in the original post, but showed no results. So here is the analysis, in which the plots below analyse the torsion about the phenyl–NO bond. You can see all the examples are either red or blue,‡ which indicates torsions of ~180 or 0°. You can perceive a very nice correlation between the length of the C-N and the N-O bonds. As the latter gets shorter, the former gets longer. This only matches the second resonance shown above and not the Robinson version! Across all known crystal structures of nitrosobenzenes, the balance between these two resonance forms changes, no doubt as a result of substituents on the benzene ring. 

A different plot which now includes the angle at the nitrogen shows very little variation in that angle (113-118°), and certainly not the much larger variation implied by Robinson’s representation. As the N-O bond gets longer, so the angle at the nitrogen opens up a bit, the lone pair on the nitrogen being repulsed by the now three lone pairs on the oxygen anion.

I have noted previously that such crystal structure mining can be used to capture many basic concepts in chemistry.[1] This is a particularly clear one, discriminating between two possible forms of curly arrow. Conversely, it shows how curly arrows can be used to simply rationalise structural variations across a series of compounds.

‡There is one outlier (it does not appear in the plots above, since these are restricted to structures with an R-factor <5%), that shows a linear Ph-N=O system (DOI: 10.5517/cc108dl8) and which may be a Robinson-like valence bond isomer of nitrosobenzene. It will be investigated further!

References

  1. H.S. Rzepa, "Discovering More Chemical Concepts from 3D Chemical Information Searches of Crystal Structure Databases", Journal of Chemical Education, vol. 93, pp. 550-554, 2015. https://doi.org/10.1021/acs.jchemed.5b00346

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The strongest bond in the universe: A crystallographic reality check?

May 25th, 2020

My previous two posts on the topic of strongest bonds have involved mono and diprotonating N2 and using quantum mechanics to predict the effect this has on the N-N bond via its length and vibrational stetching mode. Such species are very unlikely to be easily observed for verification. But how about a metal M+ instead of H+? It turns out that structures containing the fragment Ru-N≡N-Ru are a small but well studied class of organometallic. Here is a search of the CSD crystal database for this motif.

The three examples showing the shortest N-N distances are shown below.[1],[2][3]

The NN distances for these three examples are in the region of 1.1Å. There are 39 structures in total, for a variety of other transition metals, with a length <1.15Å. The angles subtended at N are close to linear;

 

For comparison, N2 itself entrained into a crystal structure has the value of ~1.096Å as measured at 80K (R-factor 0.84%)[4]) which is pretty similar to the value computed in the previous post (1.103Å).  

So the question to ask is whether any of these organometallic examples have an NN bond at least as strong as that in dinitrogen itself? Only a reliable value for the force constant will give us a clear picture, which however would be non-trivial for such species. But it does suggest that asking whether there could be a real candidate for the strongest bond in the universe other than N2 itself may not be entirely futile.

 

References

  1. Y. Sun, H. Chan, and Z. Xie, "Reaction Scope and Mechanism of Sterically Induced Ruthenium-Mediated Intramolecular Coupling of<i>o</i>-Carboranyl with Cyclopentadienyl. Synthesis and Structure of Ruthenium Complexes Incorporating Doubly Linked Cyclopentadienyl−Carboranyl Ligands", Organometallics, vol. 25, pp. 4188-4195, 2006. https://doi.org/10.1021/om0604122
  2. Y. Tanabe, S. Kuriyama, K. Arashiba, K. Nakajima, and Y. Nishibayashi, "Synthesis and Reactivity of Ruthenium Complexes Bearing Arsenic-Containing Arsenic-Nitrogen-Arsenic-Type Pincer Ligand", Organometallics, vol. 33, pp. 5295-5300, 2014. https://doi.org/10.1021/om5006116
  3. K. Abdur-Rashid, D.G. Gusev, A.J. Lough, and R.H. Morris, "Synthesis and Characterization of RuH<sub>2</sub>(H<sub>2</sub>)<sub>2</sub>(P<sup>i</sup>Pr<sub>3</sub>)<sub>2</sub> and Related Chemistry. Evidence for a Bis(dihydrogen) Structure", Organometallics, vol. 19, pp. 1652-1660, 2000. https://doi.org/10.1021/om990669i
  4. C. Dou, W. Kosaka, and H. Miyasaka, "Gate-open-type Sorption in a Zigzag Paddlewheel Ru Dimer Chain Compound with a Phenylenediamine Linker Instructed by a Preliminary Structural Change of Desolvation", Chemistry Letters, vol. 46, pp. 1288-1291, 2017. https://doi.org/10.1246/cl.170509

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The strongest bond in the universe: revisited ten years on.

May 23rd, 2020

I occasionally notice that posts that first appeared here many years ago suddenly attract attention. Thus this post, entitled The strongest bond in the universe, from ten years back, has suddently become the most popular, going from an average of 0-2 hits per day to 92 in a single day on May 22nd (most views appear to originate from India). I can only presume that a university there has set some course work on this topic and Google has helped some of the students identify my post. Well, re-reading something you wrote ten years ago can be unsettling. Are the conclusions still sound? Would I establish my claim the same way now? After all, one picks up a little more experience in ten years. So here is my revisitation.

The hypothesis was that mono and then diprotonating dinitrogen strengthened the N-N bond, in the sequence N≡N → H-N≡N+ → H-N≡N-H2+ to the point that the latter was now a candidate for the strongest known bond between two (non-hydrogen) atoms. One of my original criteria was to calculate the N-N stretching wavenumber. To get this, I had to project out the coupling between the N-N stretching mode and the H-N modes in the latter two species. In the original discussion, Igor suggested another candidate O22+ in the comments. I speculated that the heavy atom diatomic force constant might be a better way of estimating how strong the bond was rather than the stretching wavenumber, but I never followed this up! So time to do so now.

The calculations are now at the CCSD(T)/Def2-TZVPP level (FAIR DOI: 10.14469/hpc/7214).

Species Heavy atom Force constant, mDyne/Å Projected heavy atom stretch, cm-1 Bond length, Å
N≡N 45.5177 2349 1.1029
HN≡N+ 50.2662 2469 1.0983
HN≡NH2+ 56.4903 2617 1.0859
O≡O2+ 44.9542 2184 1.0510
N≡O1+ 49.0119 2365 1.0678
HN≡O2+ 50.8061 2411 1.065
HN≡C 38.4408 2234 1.175

I did learn one new trick. To project out mode mixing between the hydrogen stretch and the heavy atom stretch, the hydrogen atom masses are now set at 10,000! This has the effect of suppressing any mode mixing, but it also results in exactly the same reduced mass for the NN stretch (14.0) for the three species N≡N, H-N≡N(+) and H-N≡N-H(2+), thus facilitating a like for like comparison. Ten years ago I had also tried the other direction, setting the mass of H to 0.001. Although this latter also eliminates the mode mixing, it does not result in the same reduced masses for the NN mode. So we will stick to the heavy hydrogen projection for comparisons.

The force constant increases almost linearly on mono and then diprotonation of dinitrogen, reaching 56.5 mDyne/Å. In comparison, both O22+ and NO1+ are a little lower. Does monoprotonating NO1+ strengthen its bond? Yes, but not quite surpassing HN≡NH2+. And the neutral HN≡C, which is isoelectronic with HN≡N+, also shows a weaker bond.

So my revisitation ten years on still shows that diprotonated nitrogen has the strongest bond (presumably in the universe), as now judged by the diatomic force constant. The hunt is still on for a species where the force constant between two non-hydrogen atoms is higher. Maybe I will return in another ten years to see the state of this challenge!

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Choreographing a chemical ballet: what happens if you change one of the actors?

May 8th, 2020

Earlier, I explored the choreography or “timing”, of what might be described as the curly arrows for a typical taught reaction mechanism, the 1,4-addition of a nucleophile to an unsaturated carbonyl compound (scheme 1). I am now going to explore the consequences of changing one of the actors by adding the nucleophile to an unsaturated imine rather than carbonyl compound (scheme 2). 

                                  Scheme 1

                                  Scheme 2

For the reaction shown in Scheme 1, the maximum energy point along the reaction path involves the formation of an S-C bond (arrow 2 in scheme 1) rather than transfer of a proton. Scheme 2 has a new actor in which NH replaces O and which is a better base (i.e. has a greater affinity for a proton). The mechanism again starts with arrows 1 and 2 launching proceedings. If you watch the animation below very carefully, you will notice that arrows 3 and 4 lag behind them. This means that you have to have the blue arrows 1 and 4 as distinctly separate arrows. An alternative depiction (and in truth very probably the depiction you would find in pretty much all text books and lecture notes) would be to combine arrows 1 and 4 into the single red arrow 8. If you do this however, you loose this subtle nuance to the mechanism.

                    Animated Reaction coordinate for TS1 (scheme 2) Click to load 3D model

                     Energy along reaction coordinate for TS1 (Scheme 2)

The product of this first step is a zwitterionic (internal ion-pair) compound. This then goes on to form the S-C bond (arrows 5–7) via TS2, with the energy of this second transition state being lower than than TS1.

                            Animated reaction coordinate for TS2 (Scheme 2)

The free energy barrier for this second step is low (ΔG† 0.6 kcal/mol) because it is an ion-pair reacting to form a neutral molecule, always a facile process. Because the slowest step in this reaction (TS1) involves a proton transfer, this should now show a primary deuterium kinetic isotope effect. Indeed this is calculated to have the value 4.0 at 298K. There is a prediction for an experiment to undertake!

Species
(FAIR Data: dt5d)

Relative energy

kcal/mol
Reactant 0.0
TS1 7.7
Zwitterion 2.2
TS2 2.8
Product -12.5

To sumarise

  1. Changing a C=O group to a C=NH group changes the nature of the mechanism from concerted asynchrous to stepwise.
  2. As a result of this change, the highest energy step now involves asynchronous proton transfers rather than S-C bond formation.
  3. The curly arrows can be used to reflect these steps, with two (blue) arrows being preferred to a single (red) one.

So by expanding the conventional number of curly arrows used to include extra ones capturing asynchronicity in the reaction, one can indeed add further information to the curly arrow formalism.

This post has DOI: dt6v

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Discussion of (the) Room-temperature chemical synthesis of dicarbon – open and transparent science.

May 6th, 2020

A little more than a year ago, a ChemRxiv pre-print appeared bearing the title referenced in this post,[1] which immediately piqued my curiosity. The report presented persuasive evidence, in the form of trapping experiments, that dicarbon or C2 had been formed by the following chemical synthesis. Here I describe some of what happened next, since it perhaps gives some insight into the processes of bringing a scientific result into the open.

My curiosity at that time was because a thermal facile reaction is normally associated with a sufficiently low free energy barrier to the transition state to allow a flux of the product to form on a reasonable timescale, and at a concentration that can be e.g. trapped. Dicarbon however is normally considered a very high energy species. Its formation from a precursor bearing a triple bond in this case would involve breaking the ≡C–I bond in 11 above and replacing it by C⩸C, where the 4th bond is experimentally estimated to recover ~20 kcal/mol of energy. I estimated the bond dissociation energies and further calculated the free energies of the reactions of 1a, 11 and “C2” above, thus adding to the information available from the pre-print.

The original pre-print has now appeared as a full paper in Nature Communications, having passed through the peer review processes.[2] I can reveal here that I was one of the referees of this article. In my referee report I felt it appropriate to comment on my thermochemical observations on the reaction. I also waived my anonymity as part of this process (an option given to referees of this journal). Regarding the thermochemistry as essential to understanding this fascinating reaction and because it is not discussed in the final published article itself,[2] I decided to add this to the public record in the form of a matter arising (MA), also submitted to Nature Communications. Interestingly, such a form of response incurs no open access article processing charge (APC), unlike the communications themselves. In its acknowledgement of submission, the journal informs the submitting author that they can freely place the final author-version of the submission onto a pre-print server.‡ In a sense, this completes the first cycle of this process, since that is how it all started a year ago.[1] Accordingly, you can now judge my case for the thermochemistry[3] as a ChemRxiv pre-print. This is not yet the end of the process, since the MA itself is now subjected to peer review and the original authors can also respond, a process that can take several months. 

Until recently, the mechanisms by which any given scientific article emerges, fully formed so to speak, into the (possibly) open via a journal has tended towards opaqueness, with much of the process of assessment shrouded in anonymity. At a time of a global epidemic, with major life changing daily decisions being (hopefully) made on the basis of scientific discussion and (open?) evidence, it is I think especially pertinent to show how science can operate openly and transparently, to some extent and on occasion at least.

‡I was informed by the editor of the journal that a blog such as this can also be considered an appropriate pre-print server. Perhaps it was a sense of symmetry that made me chose the same location where this story started, whilst charting its progress here.

This post has DOI: dtwk

References

  1. K. Miyamoto, S. Narita, Y. Masumoto, T. Hashishin, M. Kimura, M. Ochiai, and M. Uchiyama, "Room-Temperature Chemical Synthesis of C2", 2019. https://doi.org/10.26434/chemrxiv.8009633.v1
  2. K. Miyamoto, S. Narita, Y. Masumoto, T. Hashishin, T. Osawa, M. Kimura, M. Ochiai, and M. Uchiyama, "Room-temperature chemical synthesis of C2", Nature Communications, vol. 11, 2020. https://doi.org/10.1038/s41467-020-16025-x
  3. H.S. Rzepa, "A Thermodynamic assessment of the reported room-temperature chemical synthesis of C2", 2020. https://doi.org/10.26434/chemrxiv.12237980.v2

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