Cyclopropanation: the mechanism of the Simmons–Smith reaction.

December 14th, 2014

These posts contain the computed potential energy surfaces for a fair few “text-book” reactions. Here I chart the course of the cyclopropanation of alkenes using the Simmons-Smith reagent,[1] as prepared from di-iodomethane using zinc metal insertion into a C-I bond.
simmonds-smith

Two reactions it can be compared with are the epoxidation of ethene using a peracid and dichlorocyclopropanation. The latter is a four-electron pericyclic process, which is thermally forbidden. The outcome there is that the two new bonds form very asynchronously to avoid transition state antiaromaticity. The former is a more complex reaction, best described as a six-electron process which allows both C…O bonds to form at the same rate. So which of these two does the Simmons–Smith mechanism correspond to?

The calculation as undertaken at a ωB97XD/Def2-TZVPD-PP (solvent=dichloromethane) level[2] shows the two C…C bonds forming at more or less the same rate. The reaction therefore resembles epoxidation rather than dichlorocyclopropanation.

SS

The intrinsic reaction coordinate (IRC)[3] is shown below, revealing a concerted and almost synchronous reaction. The synchronicity is all the more surprising given the diversity of bonds forming/breaking.
SSa
SSE

SSG

There are slight and tantalizing hints that the alkene and the I-Zn-CH2-I components initially form a weak π-complex, which then rearranges into the TS, and then again a weak complex at the end. The NCI surfaces for both are shown below, and show clear signs of dispersion-like stabilisations for both of them! The strange torus around the Zn-I bond is due to the need for a lower density threshold to filter out the covalent interactions.

Click for 3D

Click for 3D

Click for 3D

Click for 3D

References

  1. H.E. Simmons, and R.D. Smith, "A NEW SYNTHESIS OF CYCLOPROPANES FROM OLEFINS", Journal of the American Chemical Society, vol. 80, pp. 5323-5324, 1958. https://doi.org/10.1021/ja01552a080
  2. H.S. Rzepa, "C 3 H 6 I 2 Zn 1", 2014. https://doi.org/10.14469/ch/147617
  3. H.S. Rzepa, "Gaussian Job Archive for C3H6I2Zn", 2014. https://doi.org/10.6084/m9.figshare.1270441

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Posted in reaction mechanism | 1 Comment »

Halogen bonds 4: The strongest (?) halogen bond.

December 7th, 2014

Continuing my hunt, here is a candidate for a strong(est?) halogen bond, this time between Se and I.[1].
OXSELI
The features of interest include:

  1. The six-membered ring is in the chair conformation.
  2. The (relatively enormous) I…I substituent is axial!
  3. It is attached to the Se rather than the O.
  4. The Se…I distance is 2.75Å, some 1.13Å shorter than the combined atom ver der Waals radii (1.90 + 1.98 = 3.88)
  5. The Wiberg bond index is 0.42 for the Se-I bond and 0.63 for the I-I bond (at the crystal geometry). It is tending towards a symmetrical disposition of the central iodine (a feat also achieved by the iodine in the NI3 complex).
  6. The NBO E(2) perturbation involving donation from the Se lone pair into the I-I antibond is 77 kcal/mol, almost twice the value of the one involving DABCO…I-I and way above the values found for the related hydrogen bond.
  7. The B3LYP+D3/Def2-TZVPP+PP(I) optimised structure expands the Se-I bond distance to 3.04 and contracts the I-I distance to 2.81Å indicating (as with DABCO…I-I) that there may be compression of this bond induced by the lattice.
  8. The NCI surface shows a classical “strong” interaction between Se and I (blue), but significant additional features arising from the axial hydrogens that might account for the axial orientation of the Se…I-I group.
    Click for 3D

    Click for 3D

  9. For good measure, here is the complete crystal structure search, defining any non-bonded contact between any element of group six and group seven that is <0.5Å shorter than the van del Waals contact. Our candidate is on the left hand edge of the plot.
    Se-I

References

  1. H. Maddox, and J.D. McCullough, "The Crystal and Molecular Structure of the Iodine Complex of 1-Oxa-4-selenacyclohexane, C<sub>4</sub>H<sub>8</sub>OSe.I<sub>2</sub>", Inorganic Chemistry, vol. 5, pp. 522-526, 1966. https://doi.org/10.1021/ic50038a006

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Posted in crystal_structure_mining, Interesting chemistry | 7 Comments »

Halogen bonds 3: "Nitrogen tri-iodide"

December 1st, 2014

Nitrogen tri-iodide, or more accurately the complex between it and ammonia ranks amongst the oldest known molecules (1812). I became familiar with it around the age of 12-13, in an era long gone when boys (and very possibly girls too) were allowed to make such substances in their parent’s back gardens‡ and in fact in the school science laboratory,† an experiment which earned me a personal request to visit the head teacher.

With pyridine replacing the ammonia (I presume crystallographers are often reluctant to put sensitive crystals into their instruments), the polymeric structure PYDTIN is shown below[1] (see also IODMAM[2]. Each nitrogen is approximately tetrahedral. As with the DABCO/I2 complex discussed in the preceding post, it consists of chains of …N-I-N-I… units, with weak crosslinks (4.31Å) to adjacent chains. Six units of NI3 are shown below, although it is clear that the term nitrogen tri-iodide does not really begin to describe what is happening.

Click for 3D

Click for 3D

In terms of the D….X-A formalism outlined in the first post about halogen bonds, D = N, X = I and A = N. This system is in fact palindromic, since either of the N…I interactions could be described as the halogen bond. Which brings me to hydrogen bonds., D…H-A. They two adopt two forms, the first in which the proton is asymmetrically disposed to either D or A and the second where the proton exists exactly half way between. It is rather nice that this analogy also pertains for halogen bonds.

More interesting however is why? So a ωB97XD/Def2-TZVPP-PP calculation on the above unit.[3] Recollect that for DABCO-I2, the short N…I distance was in part probably due to compression resulting from attractive dispersion interchain forces. Again deprived of a full periodic boundary model, the unit above changes shape upon such calculation, and in particular the N…I…N interaction desymmetrises. Is this because of the lack of a full crystal lattice, or because e.g. a functional such as ωB97XD favours asymmetric halogen bonds? It is certainly true that for the simpler hydrogen bond, the asymmetric double-well potential and the symmetric single-well potentials often only differ by a few kcal/mol, and hence that some methods predict the same system asymmetric and others symmetric. Since we already suspect that this N…I distance is sufficiently soft that it can be perturbed by dispersion attractions elsewhere in the molecule, perhaps this is also true here?

Click for 3D

Click for 3D

I cannot here solve the issue of whether some halogen bonds exist in symmetric potentials because they intrinsically disposed to do so, or whether this is induced by the larger environment of the crystal. But it is certainly apparent that this molecule, known for 202 years now, is still of modern interest and relevance.

‡My grasp of quantities was rather vague, and I set out 2-3 mounds of the stuff on the garden path, possibly as much as 1g each. One needs to wait an hour or so to allow the mound to dry out. The first visitor to the garden following this drying out period was my mother, who had come to put the washing on the line, a line that followed exactly that of the path itself. She did not quite know what to make of the loud crack originating from her shoes, but was much more alarmed by the substantial cloud of purple vapours that enveloped her feet and slowly rose upwards. Well, if you have not read any chemistry books, what would you make of such an experience? I will also record here my other experiment in the garden. My father had put a very old fridge there, prior to arranging its permanent removal. I pondered what the refrigerant might be, and so rather optimistically sawed through the pipe with a test tube ready to collect any liquid that might flow out. It was SO2, and not un-naturally I fled the scene. This must have been at dusk, since I only returned the following morning. My parents proud and joy was a tenderly cared for lawn. That morning, it was pure white. It was bordered by campanula, which were still resolutely blue, making for a rather nice contrasting colour scheme. But with no explanation to hand to give my parents for my inadvertent garden redesign, I instead went to school. The odd thing was that when I returned that afternoon, absolutely no mention was made by either parent of the strange change in colour of the lawn (it was back to normal about two weeks later, with no permanent harm done). To this day, I have no idea what they thought might have happened. Well, if you have not read any chemistry books, what would you make of such an experience?

†I had somewhat underestimated the drying time, and so had to leave the school laboratory for my next lesson. About halfway through the next laboratory class, the new set of students started to be alarmed by the loud cracks coming from the water-pump gutter running down the middle of the laboratory bench. More to the point, the teacher did not know how to stop these noises, which continued to punctuate the rest of his class. To describe him as annoyed at the end of that class is putting it mildly. At least, he HAD read some chemistry textbooks.

References

  1. H. Hartl, and D. Ullrich, "Die Kristallstruktur von Stickstofftrijodid‐1‐Pyridin NJ<sub>3</sub> · C<sub>5</sub>H<sub>5</sub>N", Zeitschrift für anorganische und allgemeine Chemie, vol. 409, pp. 228-236, 1974. https://doi.org/10.1002/zaac.19744090212
  2. R. Hagedorn, H. Pritzkow, and J. Jander, "<i>N</i>-Iododimethylamine", Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry, vol. 33, pp. 3209-3210, 1977. https://doi.org/10.1107/s0567740877010565
  3. H.S. Rzepa, and H.S. Rzepa, "C 5 H 5 I 18 N 7", 2015. https://doi.org/10.14469/ch/191465

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Halogen bonds 3: “Nitrogen tri-iodide”

December 1st, 2014

Nitrogen tri-iodide, or more accurately the complex between it and ammonia ranks amongst the oldest known molecules (1812). I became familiar with it around the age of 12-13, in an era long gone when boys (and very possibly girls too) were allowed to make such substances in their parent’s back gardens‡ and in fact in the school science laboratory,† an experiment which earned me a personal request to visit the head teacher.

With pyridine replacing the ammonia (I presume crystallographers are often reluctant to put sensitive crystals into their instruments), the polymeric structure PYDTIN is shown below[1] (see also IODMAM[2]. Each nitrogen is approximately tetrahedral. As with the DABCO/I2 complex discussed in the preceding post, it consists of chains of …N-I-N-I… units, with weak crosslinks (4.31Å) to adjacent chains. Six units of NI3 are shown below, although it is clear that the term nitrogen tri-iodide does not really begin to describe what is happening.

Click for 3D

Click for 3D

In terms of the D….X-A formalism outlined in the first post about halogen bonds, D = N, X = I and A = N. This system is in fact palindromic, since either of the N…I interactions could be described as the halogen bond. Which brings me to hydrogen bonds., D…H-A. They two adopt two forms, the first in which the proton is asymmetrically disposed to either D or A and the second where the proton exists exactly half way between. It is rather nice that this analogy also pertains for halogen bonds.

More interesting however is why? So a ωB97XD/Def2-TZVPP-PP calculation on the above unit. Recollect that for DABCO-I2, the short N…I distance was in part probably due to compression resulting from attractive dispersion interchain forces. Again deprived of a full periodic boundary model, the unit above changes shape upon such calculation, and in particular the N…I…N interaction desymmetrises. Is this because of the lack of a full crystal lattice, or because e.g. a functional such as ωB97XD favours asymmetric halogen bonds? It is certainly true that for the simpler hydrogen bond, the asymmetric double-well potential and the symmetric single-well potentials often only differ by a few kcal/mol, and hence that some methods predict the same system asymmetric and others symmetric. Since we already suspect that this N…I distance is sufficiently soft that it can be perturbed by dispersion attractions elsewhere in the molecule, perhaps this is also true here?

Click for 3D

Click for 3D

I cannot here solve the issue of whether some halogen bonds exist in symmetric potentials because they intrinsically disposed to do so, or whether this is induced by the larger environment of the crystal. But it is certainly apparent that this molecule, known for 202 years now, is still of modern interest and relevance.

‡My grasp of quantities was rather vague, and I set out 2-3 mounds of the stuff on the garden path, possibly as much as 1g each. One needs to wait an hour or so to allow the mound to dry out. The first visitor to the garden following this drying out period was my mother, who had come to put the washing on the line, a line that followed exactly that of the path itself. She did not quite know what to make of the loud crack originating from her shoes, but was much more alarmed by the substantial cloud of purple vapours that enveloped her feet and slowly rose upwards. Well, if you have not read any chemistry books, what would you make of such an experience? I will also record here my other experiment in the garden. My father had put a very old fridge there, prior to arranging its permanent removal. I pondered what the refrigerant might be, and so rather optimistically sawed through the pipe with a test tube ready to collect any liquid that might flow out. It was SO2, and not un-naturally I fled the scene. This must have been at dusk, since I only returned the following morning. My parents proud and joy was a tenderly cared for lawn. That morning, it was pure white. It was bordered by campanula, which were still resolutely blue, making for a rather nice contrasting colour scheme. But with no explanation to hand to give my parents for my inadvertent garden redesign, I instead went to school. The odd thing was that when I returned that afternoon, absolutely no mention was made by either parent of the strange change in colour of the lawn (it was back to normal about two weeks later, with no permanent harm done). To this day, I have no idea what they thought might have happened. Well, if you have not read any chemistry books, what would you make of such an experience?

†I had somewhat underestimated the drying time, and so had to leave the school laboratory for my next lesson. About halfway through the next laboratory class, the new set of students started to be alarmed by the loud cracks coming from the water-pump gutter running down the middle of the laboratory bench. More to the point, the teacher did not know how to stop these noises, which continued to punctuate the rest of his class. To describe him as annoyed at the end of that class is putting it mildly. At least, he HAD read some chemistry textbooks.

References

  1. H. Hartl, and D. Ullrich, "Die Kristallstruktur von Stickstofftrijodid‐1‐Pyridin NJ<sub>3</sub> · C<sub>5</sub>H<sub>5</sub>N", Zeitschrift für anorganische und allgemeine Chemie, vol. 409, pp. 228-236, 1974. https://doi.org/10.1002/zaac.19744090212
  2. R. Hagedorn, H. Pritzkow, and J. Jander, "<i>N</i>-Iododimethylamine", Acta Crystallographica Section B Structural Crystallography and Crystal Chemistry, vol. 33, pp. 3209-3210, 1977. https://doi.org/10.1107/s0567740877010565

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Halogen bonds 2: The DABCO-Iodine structure.

November 30th, 2014

Pursuing the topic of halogen bonds, the system DABCO (a tertiary dibase) and iodine form an intriguing complex. Here I explore some unusual features of the structure HEKZOO[1] as published in 2012[2] and ask whether the bonding between the donor (N) and the acceptor (I-I) really is best described as a “non-covalent-interaction” (NCI) or not.

The crystal structure shows a repeating unit, with each DABCO surrounded by two I2 molecules aligned along the N-N axis, and inversely each I-I is bounded by a DABCO (not shown). These linear chains are stacked in a dislocated manner induced by aligning to optimize the dispersion interactions between the iodines and the CH groups. The most surprising aspect is the N…I distance shown as 2.42Å. The van der Waals radii of N and I are respectively 1.55 + 1.98 = 3.53Å, a contraction of 1.1Å. The covalent radii are 0.75 + 1.33 = 2.08, an elongation of 0.34Å So is this a strong (non-covalent) interaction/contraction or a stretched weak covalent bond?

I will start with a B3LYP+D3/Def2-TZVPP+PP calculation on the crystal geometry (below).

Click for 3D

Click for 3D

The short N…I distance has a computed Wiberg bond order of 0.26 (the I-I is 0.76) and an E(2) NBO donor-acceptor interaction energy of 40.1 kcal/mol. For comparison, the E(2) energies for conventional OH…O hydrogen bonds are around 10 kcal/mol. This makes the halogen bond a pretty strong interaction! But is it strong enough to call a bond? Indeed, do we have any means of deciding where the transition from a strong interaction to a weak bond occurs?

A NCI analysis is shown below. This analysis filters out electron densities above 0.05au (which are considered as covalent values) and shows only the properties of the reduced density gradients below this value. The dispersion attractions between the DABCO hydrocarbon chains and the iodine molecules are very apparent, but the N…I is encircled with a strange feature, normally only seen for covalent bonds or transition state breaking/forming bonds. A strong hydrogen bond for example would show up as blue, and not this strange torus.

Click for 3D

Click for 3D

Reducing the threshold for covalent densities to be filtered out to 0.03au eliminates the N…I feature (it is now covalent by definition so to speak), but the I-I feature remains. One can see here that this NCI analysis does rather arbitrarily depend on what one considers the covalent density threshold to be, and as one moves up the periodic table, this density changes. What should the density for eg a N…I interaction/bond actually be? The value appropriate for N (0.05) or I (< 0.03)?

Click for 3D

Click for 3D

Next, I show the optimised geometry of the system above.[3] This is not a periodic boundary calculation and this lack of a surrounding environment is highlighted by the change in the structure. The N…I distance lengthens, and the iodines which have no DABCO to interact with lengthen more. One might conclude that the short N…I distance measured in the solid state structure is due to some degree of N…I compression induced by the linear chains of I-I…DABCO…I-I…DABCO…I-I aligning to maximise the interchain dispersion attractions. Thus the N…I “bond/interaction” is really a co-operative effect between the N…I atoms and the extended 3D structure of the molecule. The N…I contraction of 1.1Å noted above is in part due to the intrinsic halogen bond, but also in part due to dispersion attractions elsewhere!
DAB-opt

So it does rather seem as if the DABCO-I2 complex sits very much in that awkward region in which the contracted N…I distance could either be described as a weak bond or a strong interaction.‡. Just like the infamous H…H bond in cis-butene, one cannot just regard a bond as a purely localised phenomenon, one must also take into account what is happening elsewhere in the total system. Halogen bonds could also be regarding as filling the gap spanned by recognised covalency and recognised hydrogen bonds. I note in passing that another “awkward” bond is the 4th in the diatomic C2[4] that has a bond energy of about 17 kcal/mol, again weak for a normal bond and strong for an interaction.

In my next post on this theme, I will deal with another halogen bond that is found in a famous molecule known for a long time and which has another weird property.

‡Postscript. An ELF analysis reveals the following basin centroids. Basin 1 integrates to 2.00 electrons, basin 2 to 1.92. The asymmetry in the position of the basin centroid towards the nitrogen suggests it is not an equally shared covalent bond, as indeed the Wiberg bond order noted above also indicates. The I…I basin integrates to 1.86 electrons, indicating slightly reduced bonding (by donation into the sigma; orbital).
DABCO-I2-ELF

References

  1. Peuronen, A.., Valkonen, A.., Kortelainen, M.., Rissanen, K.., and Lahtinen, M.., "CCDC 879935: Experimental Crystal Structure Determination", 2013. https://doi.org/10.5517/ccyjn03
  2. A. Peuronen, A. Valkonen, M. Kortelainen, K. Rissanen, and M. Lahtinen, "Halogen Bonding-Based “Catch and Release”: Reversible Solid-State Entrapment of Elemental Iodine with Monoalkylated DABCO Salts", Crystal Growth & Design, vol. 12, pp. 4157-4169, 2012. https://doi.org/10.1021/cg300669t
  3. H.S. Rzepa, "Gaussian Job Archive for C12H24I8N4", 2014. https://doi.org/10.6084/m9.figshare.1254779
  4. D. Danovich, P.C. Hiberty, W. Wu, H.S. Rzepa, and S. Shaik, "The Nature of the Fourth Bond in the Ground State of C<sub>2</sub>: The Quadruple Bond Conundrum", Chemistry – A European Journal, vol. 20, pp. 6220-6232, 2014. https://doi.org/10.1002/chem.201400356

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Posted in Interesting chemistry | 5 Comments »

Halogen bonds: Part 1.

November 29th, 2014

Halogen bonds are less familiar cousins to hydrogen bonds. They are defined as non-covalent interactions (NCI) between a halogen atom (X, acting as a Lewis acid, in accepting electrons) and a Lewis base D donating electrons; D….X-A vs D…H-A. They are superficially surprising, since both D and X look like electron rich species. In fact the electron distribution around X-X (A=X) is highly anisotropic, with the electron rich distribution (the “donor”)  being in a torus encircling the bond, and an electron deficient region (the “acceptor”) lying along the axis of the bond.

I will start this simple exploration of halogen bonds by a crystal structure search, defined as below, where A in the above definition is also any halogen, the donor D is a tri-alkyl nitrogen donating via a lone pair, the green contact is defined as an intermolecular distance equal to or shorter than the sum of the van der Waals radii together with an angle subtended as N…7A…7A.

halogen-search

The result of such a search is shown below:

halogen-search1
There are surprises.

  1. The sparsity of hits. If the search is repeated with A = N, O or S, only six further hits are obtained, all with A=N and X=I with one example of X=Br.
  2. There is a hot-spot at an N…I distance of 2.37Å, a massive 1.2Å shorter than the combined van der Waals radii of N and I, and with a linear N…I-I angle.

This next search replaces A with a carbon instead of a halogen. The hot-spot moves to ~2.8Å, still much shorter than the combined van der Waals radii,  and there are rather more hits this time.‡

N-IC

I will next start with a simple exploration of how the electron density on I2 changes when it accepts an electron from a donor D (ωB97XD/Def2-TZVPP-PP calculation). The following is an electron density difference isosurface (0.002au) showing how the density changes. The red phase is increased density, which adds exo to the bond, and the blue is decreased density, mostly at the iodine atom but also in the centre of the bond. These changes have axial symmetry along the axis of the I-I bond.

halogen-search1

As usual, if you want to view a 3D model of this surface, click on the graphic above.

This next difference map shows the inverse, i.e. what happens when an electron is removed from I2 to form a radical cation. Again blue shows decreased density, and this is not axially symmetric, coming from the π-system (more specifically just one of the π-MOs;  the orthogonal π-manifold actually gains red density). This is a nice way of showing that  I2  accepts electrons into the σ-manifold and looses them from the π-manifold. In other words, the density responds in a very anisotropic way to addition or loss of electrons.†

halogen-search1

In part 2, I will focus on one of the examples, HEKZOO[1] as published in 2012[2]. This is a complex between the base DABCO and molecular iodine, in which the DABCO donates electrons into that I2 σ-manifold.

‡There are only three significant hits with D=di-alkyloxygen rather than nitrogen. The first two[3],[4] involve X-A=I-I with a D…X distance of 2.8Aring; and the third X-A=Cl-Cl.

†I have now added also the density difference map for the base DABCO as a model for the donor D. Note that for this base, when an electron is lost to form the radical cation, the density reduces not just at the nitrogen lone pairs, but also the adjacent C-C bonds.

DABCO Density

This post is the first I have written since hearing the very sad news about the death of Paul Schleyer. He was a frequent commentator on these posts, and his towering presence over the last sixty years in chemistry will be sorely missed.

References

  1. Peuronen, A.., Valkonen, A.., Kortelainen, M.., Rissanen, K.., and Lahtinen, M.., "CCDC 879935: Experimental Crystal Structure Determination", 2013. https://doi.org/10.5517/ccyjn03
  2. A. Peuronen, A. Valkonen, M. Kortelainen, K. Rissanen, and M. Lahtinen, "Halogen Bonding-Based “Catch and Release”: Reversible Solid-State Entrapment of Elemental Iodine with Monoalkylated DABCO Salts", Crystal Growth & Design, vol. 12, pp. 4157-4169, 2012. https://doi.org/10.1021/cg300669t
  3. H. Bock, and S. Holl, "CCDC 147854: Experimental Crystal Structure Determination", 2001. https://doi.org/10.5517/cc4yvhd
  4. Walbaum, C.., Pantenburg, I.., and Meyer, G.., "CCDC 837899: Experimental Crystal Structure Determination", 2012. https://doi.org/10.5517/ccx3x0x

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A computed mechanistic pathway for the formation of an amide from an acid and an amine in non-polar solution.

November 12th, 2014

In London, one has the pleasures of attending occasional one day meetings at the Burlington House, home of the Royal Society of Chemistry. On November 5th this year, there was an excellent meeting on the topic of Challenges in Catalysis, and you can see the speakers and (some of) their slides here. One talk on the topic of Direct amide formation – the issues, the art, the industrial application by Dave Jackson caught my interest. He asked whether an amide could be formed directly from a carboxylic acid and an amine without the intervention of an explicit catalyst. The answer involved noting that the carboxylic acid was itself a catalyst in the process, and a full mechanistic exploration of this aspect can be found in an article published in collaboration with Andy Whiting’s group at Durham.[1] My after-thoughts in the pub centered around the recollection that I had written some blog posts about the reaction between hydroxylamine and propanone. Might there be any similarity between the two mechanisms?

amide

That mechanism can be represented as above, which (as per the hydroxylamine mechanism) comprises three transition states and two intermediates. The original study[1] reported just the one TS1. Editing out the starting coordinates from the PDF-based supporting information (the process is not always easy) enabled an IRC (intrinsic reaction coordinate) for TS1 to be easily computed.[2]

origa

origa
This reveals that TS1 is not the complete story, there is still much of the reaction left to complete. The energy profile is charted (using the ωB97XD/6-311G(d,p/SCRF=p-xylene method) according to the scheme above as reactants ⇒ TS1 ⇒ Intermediate 1 ⇒ TS2 ⇒ Tetrahedral intermediate ⇒ TS3 ⇒ products. Computed properties for this more detailed pathway are transcluded here from the digital repository[3] and appear at the end of this post.

  1. TS1 yields what might be called a zwitterionic intermediate. However, this has a relatively small dipole moment (5.7D). Thus, against accepted wisdom, such apparently ionic intermediates CAN be involved in reactions occurring in non-polar solvents!
  2. TS2 is rather unexpected, involving synchronous proton transfer coupled to anomerically related C-OH bond rotation. This rotation changes the anomeric interactions with the adjacent substituents; in my experience I have never before seen a reaction mode quite like this one!
  3. TS3 collapses the tetrahedral intermediate by synchronous proton transfer and C-O bond cleavage, and is (in this model) the rate determining step.  The free energy barrier corresponds to a half-life at 298K of about half an hour.
  4. The product is calculated as exoenergic with respect to reactants,; the reaction does drive to form an amide (and any catalysis of course will not influence that final outcome, only its kinetics).

If you read the original article[1] you will realise the above only scratches the surface of the many fascinating properties of this apparently very simple reaction. Thus, not addressed above is why amides are only formed in certain solvents (xylene for example) but not others. The solvent may have a specific role to play which is not modelled simply by its continuum dielectric or its boiling point. There is much else that could be said.

References

  1. H. Charville, D.A. Jackson, G. Hodges, A. Whiting, and M.R. Wilson, "The Uncatalyzed Direct Amide Formation Reaction – Mechanism Studies and the Key Role of Carboxylic Acid H‐Bonding", European Journal of Organic Chemistry, vol. 2011, pp. 5981-5990, 2011. https://doi.org/10.1002/ejoc.201100714
  2. H.S. Rzepa, "C21H21NO4", 2014. https://doi.org/10.14469/ch/74636
  3. H.S. Rzepa, "A computed mechanistic pathway for the formation of an amide from an acid and an amine in non-polar solution.", 2014. https://doi.org/10.6084/m9.figshare.1235300

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Posted in reaction mechanism | 6 Comments »

The solvation of ion pairs.

November 6th, 2014

Solvolytic mechanisms are amongst the oldest studied, but reproducing their characteristics using computational methods has been a challenging business. This post was inspired by reading Steve Bachrach’s post, itself alluding to this aspect in the title “Computationally handling ion pairs”. It references this recent article on the topic[1] in which the point is made that reproducing the features of both contact and solvent-separated ion pairs needs a model comprising discrete solvent molecules (in this case four dichloromethane units) along with a continuum model.

The system is a methylated glucose with a triflate in the anomeric position, and the reaction is the ionisation of the triflate to form an oxenium cation and a triflate anion, this occurring in dichloromethane as solvent. The resulting ion pair can only be modelled if around four explicit solvent molecules are included in the model. The normal wisdom is that explicit hydrogen bonds are not replicated by a continuum solvent model. But relatively non-polar molecules such as dichloromethane are not normally thought of as strong hydrogen bond donors or acceptors. I thought I would take the geometries of the initial covalently bound triflate and the solvent-separated species as reported [1] and subject both to a non-covalent-interaction analysis (NCI). This analyses the electron density in the molecule, and converts a property of the second derivatives of that density into a colour-code surface. Here, blue emerges mostly for hydrogen bonds, whereas weaker interactions such as dispersion attraction emerge as green. The first such diagram relates to covalently bound triflate.
R

You can see from this that most of the NCI features are coded green; it is a typical dispersion map. Next, the solvent-separated ion-pair. There is a lot more (pale) blue. This indicates that explicit (albeit weak; strong H-bonds emerge as dark blue) hydrogen bond interactions are indeed set up. This in turn might explain why a simple continuum model does not properly account for this species.

SSIP

Because these are rather globular molecules, with the NCI features distributed internally, it is important that one views these interactively and not simply from one perspective in a static diagram. So do take the opportunity to click on the two images above to load such rotatable views. And then you can explore for yourself exactly where those blue regions occur, and whether you would have classified them as hydrogen bonds without the benefit of the NCI visualisation helping you! The lesson is that a zwitterionic molecule strongly polarises and hence strengthens any weak hydrogen bonds present, meaning they can no longer be dismissed.

References

  1. T. Hosoya, T. Takano, P. Kosma, and T. Rosenau, "Theoretical Foundation for the Presence of Oxacarbenium Ions in Chemical Glycoside Synthesis", The Journal of Organic Chemistry, vol. 79, pp. 7889-7894, 2014. https://doi.org/10.1021/jo501012s

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Blasts from the past. A personal Web presence: 1993-1996.

November 1st, 2014

Egon Willighagen recently gave a presentation at the RSC entitled “The Web – what is the issue” where he laments how little uptake of web technologies as a “channel for communication of scientific knowledge and data” there is in chemistry after twenty years or more. It caused me to ponder what we were doing with the web twenty years ago. Our HTTP server started in August 1993, and to my knowledge very little content there has been deleted (it’s mostly now just hidden). So here are some ancient pages which whilst certainly not examples of how it should be done nowadays, give an interesting historical perspective. In truth, there is not much stuff that is older out there!

  1. This page was written in May 1994 as a journal article, although it did have to be then converted into a Word document to actually be submitted.[1] Because it introduced hyperlinks to a chemical audience, we wanted to illustrate these in the article itself! Hence permission was obtained from the RSC for an HTML version to be “self-archived” on our own servers where the hyperlinks were supposed to work (an early example of Open Access publishing!). I say supposed because quite a few of them have now “decayed”. We were aware of course that this might happen, but back in 1994, no-one knew how quickly this would happen. What is interesting is that the HTML itself (written by hand then) has survived pretty well! I will leave you to decide how much the message itself has decayed.
  2. This HTML actually predates the above; it was written around November 1993 and represented the very first lecture notes I converted into this form (on the topic of NMR spectroscopy). A noteworthy aspect is the scarce use of colour images. At the start of 1994, the bandwidth available on our campus was pretty limited (the switches were 10 Mbps only) and a request went out to reduce the bit-depth of any colour images to 4-bits to help conserve that bandwidth! I rather doubt anyone took much notice however, and the policy was forgotten just a few months later.
  3. In 1996, I had two visitors to the group, Guillaume Cottenceau, a french undergraduate student, and Darek Bogdal, a Polish researcher who wanted to learn some HTML. Together they produced this, which was an interactive tutorial to accompany the NMR lecture notes previously mentioned. These pages introduce the Java applet (yes, it was very new in 1996), which Guillaume had written and which Darek then made use of. And hey, what do you know, the applet still works (although you might have to coerce your browser into accepting an unsigned applet).
  4. Here is a programming course that I had been running with Bryan Levitt for a few years, now recast into HTML web pages some time in 1994-5. This particular project I still hold dear, since it expanded upon the NMR lectures by getting the students to synthesize a FID (free induction decay) using the program they wrote, and then perform a Fourier Transform on it. I even encouraged students to present their results in HTML (I cannot now remember how many did). This link is to the computing facilities we offered students in 1994 for this project, ah those were the times! In 1996, the programming course was replaced by one on chemical information technologies, and here students were most certainly expected to write HTML. Some of the best examples are still available. And to illustrate how things happen in cycles, that course itself is now gone to be replaced by, yes, a programming course (but using Python, and not the original Fortran).
  5. In tracking down the materials for the programming course described above, I re-discovered something far older. It is linked here and is (some of) the Fortran source code I wrote as a PhD student in 1974 1972. So I will indulge in a short digression. My Ph.D. involved measuring rate constants, and the accepted method for analysing the raw kinetic data was using graph paper. For first order rate behaviour, this required one to measure a value at time=∞, which is supposed to be measured after ten half-lives. I was too impatient to wait that long, and worked out that a non-linear least squares analysis did not require the time=∞ value; indeed this value could be predicted accurately from the earlier measurements. So in 1974, I wrote this code to do this; no graph paper for me! Also for good measure is a least squares analysis of the Eyring equation. And you get proper standard deviations for your errors. In retrospect I should have commercialised this work, but in 1974, almost no-one paid money for software! What a change since then. I must try recompiling this code to see if it still works! And for good measure, here is a Huckel MO program I wrote in 1984 or earlier (I did compile this recently and found it works) and here is a little program for visualising atomic orbitals.
  6. In January 1994, I was asked to create a web page for the WATOC organisation. This certainly predated the web sites for e.g. the RSC, the ACS, indeed famous sites such as the BBC and Tesco (a large supermarket chain) which only started up in mid 1994. The WATOC site itself moved a few years ago.
  7. This is one of those wonderfully naive things I started in 1994, and which did not last long (in my hands). Nowadays, the concept lives on as MOOCs. Note again the almost complete expiry of the hyperlinks.
  8. This is a project we also started in 1994, Virtual reality[2],[3]. The idea was that if HTML was text-markup, VRML was going to be 3D markup. VRML itself never quite caught on, but it is having a new life as a 3D printing language!
  9. And by 1995, I felt confident enough in my ability to (edit) HTML, that we started a virtual conference in organic chemistry (we did four of them in the end). I remember the first one involved contributors sending me a Word version of their poster, and I did all the work in converting it into HTML. Such virtual conferences still run, but in truth most participants still prefer to travel long distances to go drink a beer with their chums, rather than hack HTML.

I am going to stop now, since this is far too much wallowing in the past. But at least all this stuff is not (yet) lost to posterity.

References

  1. H.S. Rzepa, B.J. Whitaker, and M.J. Winter, "Chemical applications of the World-Wide-Web system", Journal of the Chemical Society, Chemical Communications, pp. 1907, 1994. https://doi.org/10.1039/c39940001907
  2. O. Casher, and H.S. Rzepa, "Chemical collaboratories using World-Wide Web servers and EyeChem-based viewers", Journal of Molecular Graphics, vol. 13, pp. 268-270, 1995. https://doi.org/10.1016/0263-7855(95)00053-4
  3. O. Casher, C. Leach, C.S. Page, and H.S. Rzepa, "Advanced VRML based chemistry applications: a 3D molecular hyperglossary", Journal of Molecular Structure: THEOCHEM, vol. 368, pp. 49-55, 1996. https://doi.org/10.1016/s0166-1280(96)90535-7

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More simple experiments with crystal data. The pyramidalisation of nitrogen.

November 1st, 2014

We are approaching 1 million recorded crystal structures (actually, around 716,000 in the CCDC and just over 300,00 in COD). One delight with having this wealth of information is the simple little explorations that can take just a minute or so to do. This one was sparked by my helping a colleague update a set of interactive lecture demos dealing with stereochemistry. Three of the examples included molecules where chirality originates in stereogenic centres with just three attached groups. An example might be a sulfoxide, for which the priority rule is to assign the lone pair present with atomic number zero. The issue then arises as to whether this centre is configurationally stable, i.e. does it invert in an umbrella motion slowly or quickly.  My initial intention was to see if crystal structures could cast any light at all on this aspect.

pyramidal

Central atom has three bonded atoms as C, of which either all three must themselves have four attached atoms, or one can have just three attached atoms as shown above, along with acyclic character for the three bonds attached to the central atom, R ≤ 0.1, not disordered and no errors.

Using the search definition above for R3N one gets the result below. It shows a hot spot for an angle subtended at the nitrogen of ~111°, indicating a pyramidal nitrogen. But how easily is that perturbed? (which is almost like asking how easily can it invert its configuration?).

R3N, all sp3 attached carbons

A perturbation can be applied by changing just one of the attached carbons as having three attached atoms of its own (sp2 hybridised). The response is that the hot spot moves to 120° (below). Of course now this includes compounds such as amides and the like. But we have learnt that it takes just one such attached sp2 hybridised carbon to planarize an adjacent nitrogen.

R3N-1sp2-2sp3

The control experiment will now be to apply the same test to a P. The hot spot moves from ~99° (P with three sp3 carbons attached) to ~103° (P with two sp3 and one sp2). This reminds us that the overlap and energy-match between a p-orbital on carbon to an adjacent p-orbital on nitrogen is good, whereas the same overlap/energy match to a p-orbital on P is significantly less so.
R3P-sp3

R3P-1sp2-2sp3

One gets the same result when the central atom is S; the hotspot moves from ~102° to ~105°. Unfortunately, not enough compounds are known for a tri-substituted oxygen compounds to see how this element responds.

R3S-sp3R3S-1sp2-2sp3

My point in illustrating these statistics is to show how much text-book chemistry can be recovered simply by a few quick explorations of crystal structures. One could even argue that much introductory chemistry could be taught by reference to the statistics of such structures.

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