Posts Tagged ‘condensation’

Organocatalytic cyclopropanation of an enal: (computational) mechanistic understanding.

Saturday, August 25th, 2018

Symbiosis between computation and experiment is increasingly evident in pedagogic journals such as J. Chemical Education. Thus an example of original laboratory experiments[1],[2] that later became twinned with a computational counterpart.[3] So when I spotted this recent lab experiment[4] I felt another twinning approaching.

The reaction under consideration is that between dec-2-enal and 2,4-dinitrobenzyl chloride as catalysed by an α,α-diphenylprolinol trimethylsilyl ester with addition of further base (di-isopropylamine?). The proposed mechanism can be seen in figure 7‡ of the journal article[4] and also scheme 2 of an earlier article.[5] The following is my interpretation of their published mechanism (the compound numbering is the same as in Figure 7).

  1. The initiating step is the condensation between the alkyl enal (1) and the prolinol derivative (3), with elimination of water and the formation of a positive iminium cation (5). One might wonder at this stage what the counter ion to this cation is.
  2. 5 then reacts with 2,4-dinitrobenzyl chloride (2) with apparent elimination of HCl to form 6. This corresponds to 1,4-Michael addition to 5 with the formation of the first new  C-C bond and the creation of two new stereogenic centres.
  3. 6 then cyclises to form a second new C-C bond and a third new stereogenic centre as in 7.
  4. 7 is then hydrolysed to give the final product 4.

A total of three (starred) stereogenic centres are therefore created in 4, implying 23 = 8 steroisomers, arranged as four diastereomers and their enantiomers. A computational mechanistic analysis might strive to cast light on the following questions.

  • Is the sequence shown in figure 7 reasonable? If not can a more reasonable cycle be constructed that has energetics corresponding to a facile reaction at 0°C?
  • What are the predicted relative yields of the four possible diastereomeric products and do they match those observed?
  • If  R=α,α-diphenylprolinol trimethylsilyl ester, then this fourth chiral centre increases the total number of stereoisomers to 16, arranged in eight pairs of diastereomers. Does this result in the diastereomers of 4 forming with an excess of one enantiomer over the other (an ee ≠ 0)?

This post addresses just the first question (R=R’=H, R”=isopropylamine) leaving the other two questions for later analysis.

My analysis (figure above)♥ of the mechanism, as cast for computational analysis†, differs in various details from Figure 7/Scheme 2 of the published articles.[4],[5]

  1. The issue of defining a counterion to 5 is solved by in fact starting the cycle with proton abstraction from 2 by di-isopropylamine♦ to form a benzylic anion, as stabilized by the 2,4-dinitro groups and with the positive counter-ion being the protonated amine base.
  2. The next step is reaction between 1 and 3 to form an aminol 10, a tetrahedral intermediate.
  3. To remove water from this to form an iminium cation 5, one has to protonate the hydroxy group and this can now be done using the cationic ammonium species formed in step 5 above.
  4. The benzylic anion can now react with the iminium cation to form the first C-C bond and the first two stereocentres via 1,4-Michael addition to form 6
  5. The species 6 can now eliminate chloride anion to form the cyclopropyl iminium cation/anion pair 7, generating the 3rd stereogenic centre.
  6. Hydrolysis forms the product 4 and returns the system to the starting point in the catalytic cycle.
  7. Also included is whether an alternative mechanism is viable, involving elimination of Cl– from 8 to form a “carbene”, which could then potentially add to the alkene in 1.

Species (transition state)

FAIR Data DOI
10.14469/hpc/4642

ΔG273.15, Hartree
(ΔΔG‡273.15, kcal/mol)

Structure
(click for 3D model)
Reactants -1837.174744♣ (0.0)
TS1 -1837.150502 (15.2)
TS2 -1837.154923 (12.4)
TS3 -1837.147927 (16.8)
TS4 -1837.175723 (-0.6)
TS5 -1837.101534 (45.9)

The (relative) free energies of the transition states at the B3LYP+GD3BJ/6-311G(d,p)/SCRF=chloroform level shown in the table above (click on the thumbnail images to show the 3D model of each transition state) reveal that the highest point corresponds to TS3, a C-C bond forming reaction. This is noteworthy because it constitutes the reaction between an ion-pair, albeit ions which are both heavily stabilized by delocalisation. Since the reaction is known to proceed over 3 hours at 0°C, the activation barrier of 16.8 kcal/mol is also entirely reasonable. TS5, the putative formation of a carbene from the benzyl chloride, has a very high barrier and in fact cyclises to form 9. This pathway can therefore be safely ignored.

The next stage would be to investigate the stereochemical implications of this mechanism (atoms in 4 marked with a *) using the actual substituents for R and R’. Because the mechanism includes ion-pairs throughout, this does actually present some tricky issues. Unlike molecules with covalent bonds, where the shapes are relatively easy to predict, ion-pairs are more flexible and can often adopt a variety of poses, the relative energy of which is frequently determined simply by the magnitudes of their dipole moments.[6] If I manage to sort this out, I will report back here.

‡I would love to show you figure 7 here, but the publisher asserts that I would need to pay them $87.75 to do so and so you will have to acquire the article yourself to see it.

†Various guiding rules include constructing the entire catalytic cycle using exactly the same number of atoms so that the cycle can show only relative (free) energies and using neutral ion-pair models rather than just charged species alone.

♥Almost all the chemical diagrams on this blog for some ten years now have been in SVG (scalable vector graphics) format. Most modern web browsers for a number of years now have had excellent support for SVG. Until recently SVG could not be generated directly from a drawing program such as e.g. ChemDraw. Instead I saved as EPS (encapsulated postscript) and then used a program called Scribus to convert to SVG. In fact with Chemdraw V18.0, the direct conversion to SVG seems to be working very well, including honoring color maps. To scale up a diagram, click on it to open a new browser window containing only it and then use the browser zoom-in control to magnify it. Unlike e.g. a pixel image, SVG images magnify/scale correctly.

♣This relates to metadata as described in this post in performing a global search of any species matching this Gibbs Energy.

♦If the mechanism is set up without any base, then proton abstraction must occur directly from the benzyl chloride. Under these circumstances, the barrier for proton removal is 27.5 kcal/mol, whilst that for C-C bond formation is only 13.6.

References

  1. A. Burke, P. Dillon, K. Martin, and T.W. Hanks, "Catalytic Asymmetric Epoxidation Using a Fructose-Derived Catalyst", Journal of Chemical Education, vol. 77, pp. 271, 2000. https://doi.org/10.1021/ed077p271
  2. J. Hanson, "Synthesis and Use of Jacobsen's Catalyst: Enantioselective Epoxidation in the Introductory Organic Laboratory", Journal of Chemical Education, vol. 78, pp. 1266, 2001. https://doi.org/10.1021/ed078p1266
  3. K.K.(. Hii, H.S. Rzepa, and E.H. Smith, "Asymmetric Epoxidation: A Twinned Laboratory and Molecular Modeling Experiment for Upper-Level Organic Chemistry Students", Journal of Chemical Education, vol. 92, pp. 1385-1389, 2015. https://doi.org/10.1021/ed500398e
  4. M. Meazza, A. Kowalczuk, S. Watkins, S. Holland, T.A. Logothetis, and R. Rios, "Organocatalytic Cyclopropanation of (<i>E</i>)-Dec-2-enal: Synthesis, Spectral Analysis and Mechanistic Understanding", Journal of Chemical Education, vol. 95, pp. 1832-1839, 2018. https://doi.org/10.1021/acs.jchemed.7b00566
  5. M. Meazza, M. Ashe, H.Y. Shin, H.S. Yang, A. Mazzanti, J.W. Yang, and R. Rios, "Enantioselective Organocatalytic Cyclopropanation of Enals Using Benzyl Chlorides", The Journal of Organic Chemistry, vol. 81, pp. 3488-3500, 2016. https://doi.org/10.1021/acs.joc.5b02801
  6. J. Clarke, K.J. Bonney, M. Yaqoob, S. Solanki, H.S. Rzepa, A.J.P. White, D.S. Millan, and D.C. Braddock, "Epimeric Face-Selective Oxidations and Diastereodivergent Transannular Oxonium Ion Formation Fragmentations: Computational Modeling and Total Syntheses of 12-Epoxyobtusallene IV, 12-Epoxyobtusallene II, Obtusallene X, Marilzabicycloallene C, and Marilzabicycloallene D", The Journal of Organic Chemistry, vol. 81, pp. 9539-9552, 2016. https://doi.org/10.1021/acs.joc.6b02008

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A tutorial problem in stereoelectronic control. A Grob alternative to the Tiffeneau-Demjanov rearrangement?

Saturday, November 28th, 2015

In answering tutorial problems, students often need skills in deciding how much time to spend on explaining what does not happen, as well as what does. Here I explore alternatives to the mechanism outlined in the previous post to see what computation has to say about what does (or might) not happen.

TD

I start with posing the question what does the chloride counter-ion do? If you are aware of the literature on computational reaction mechanisms, you may note that where ionic species are involved, one of the ions is often excluded from the calculations. Here for example, the pertinent reacting species is a diazonium cation, but the anion would likely not be mentioned, and the calculation would be performed as a charged cation (the physically unrealistic charge=1 in the input file!). This is because of an awkward difficulty with ion-pairs. There is no formal bond between the two charged fragments (unless a zwitterion) and so it is not entirely obvious quite where to place the counter-ion. In the diagram above, position 1 is where it was in my first exploration, but with knowledge that it might form a hydrogen bond to an acidic hydrogen, one could also perhaps place it into positions 2 or 3. In 2, as shown by the blue arrows and product above, an entirely different reaction occurs known as the Grob fragmentation.[1] In fact as a di-carbonyl compound, it can then participate in an acid-catalysed aldol condensation and this can lead to the same product as the original Tiffeneau-Demjanov rearrangement, albeit with loss of stereochemical integrity. So it might be worth effort in explaining whether this alternative is likely (in other words how robust the likely stereochemical integrity of the product is).

System Relative TS free energy TS Dipole moment DataDOI
1 0.0 17.7 [2]
2 1.4 24.2 [3]
3 3.7 29.3 [4]

The energies of the three located transition states increase with the dipole moment; as the counter-ion moves further from the positive charge, its position becomes less stable. Still, route 2 is not that much higher in energy. Time for an IRC (intrinsic reaction coordinate) to explore what actually does happen during route 2, the possible Grob rearrangement.

grob1

The reaction animation above shows the required Grob characteristic, the green bond breaking. But instead of the OH then de-protonating, the hydrogen stays in place and instead the Tiffeneau-Demjanov migration takes place. This will require removal of a different proton and indeed in the latter stages, the chloride anion starts off in its determined journey to do so.

GrobDM

The variation in dipole moment as the reaction proceeds is fascinating. At IRC -6, it reaches a minimum, but then reverses itself in hunt of a better way of reducing the dipole moment.

What about 3? This is slightly artificial, since the real system has a methoxy group here, which would inhibit this route. One can still learn chemistry though. The hydrogen bond formed from chloride to the OH encourages the anomeric effect to form a partial oxy-anion, which in turn encourages the red bond to break rather than the green one. But in fact no complete proton transfer happens, and the reaction reaches a non-productive cul-de-sac. 

Alt1

So, to conclude, there is no Grob fragmentation! Instead, a slightly confused Tiffeneau-Demjanov migration occurs in a rather more roundabout manner than previously. We have explored here just TWO reaction trajectories. A more statistical exploration of the trajectory landscape will give us a more complete picture, but I rather fancy that would be very well above the call of duty required to answer a stereochemical problem!

References

  1. C.A. Grob, and W. Baumann, "Die 1,4‐Eliminierung unter Fragmentierung", Helvetica Chimica Acta, vol. 38, pp. 594-610, 1955. https://doi.org/10.1002/hlca.19550380306
  2. H.S. Rzepa, "C 8 H 13 Cl 1 N 2 O 4", 2015. https://doi.org/10.14469/ch/191653
  3. H.S. Rzepa, "C 8 H 13 Cl 1 N 2 O 4", 2015. https://doi.org/10.14469/ch/191654
  4. H.S. Rzepa, "C 8 H 13 Cl 1 N 2 O 4", 2015. https://doi.org/10.14469/ch/191655

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WATOC2014 Conference report. Emergent themes.

Thursday, October 9th, 2014

This second report highlights two “themes”, or common ideas that seem to emerge spontaneously from diversely different talks. Most conferences do have them.

The first is “embedding“, which in this context means treating different parts of a probably complex molecular system at different levels of theory. Thus Emily Carter in her plenary described how a periodic crystal treated by density functional theory, or DFT could have an embedded component in which the electronic structures are described instead by multi-reference correlated wave functions (CAS-PT2). She illustrated this by discussing what happens when a triplet state oxygen molecule approaches the surface of an aluminium crystal, and (mostly) dissociates into surface bound oxygen atoms with Al-O bonds. The spin state of the oxygen changes smoothly to an overall singlet, with a rapid transfer of charge at the saddle point in the potential energy surface. The numbered of embedded Al atoms had to be at least a cluster of 14 to reproduce the observed reaction barriers (DFT on its own gets a zero barrier!). This sort of study is important in understanding the details of what is happening in metal surface catalysis.

Arieh Warshel then addressed the same theme with his own talk entitled Multiscale Modeling of Complex Biological Systems and Processes. Here you got quantum embedding in a mechanical force field description of some very large molecules. This was a broad brush talk, but what I did get out of it was the concept of asymmetry in molecular systems. Whereas an organic chemist thinks of asymmetry as often relating to just a single chiral carbon centre in a molecule, nature operates on vaster scales. Thus the enzyme ATPase has a molecular axle or spindle, which rotates to assemble the phosphate groups one at a time. This spindle rotates asymmetrically, i.e. always in a specific direction, and Warshel attempts to describe the origins of this rotational asymmetry at a molecular level. Well, this is Nobel prize winning stuff! He followed this up with filaments that “walk” along surfaces in one (asymmetric) direction, first lifting up one point of attachment, and then re-attaching at a different point such that the filament develops a clear sense of direction in its walk. This of course is all done with molecular dynamics, and (I think) has its origins in subtle electrostatics.

Stefan Grimme in his plenary also described dynamic processes, this time those that happen in a mass spectrometer when a molecule is ionised by electron impact. Removal of an electron produces a complex set of ionised states, in which many different single bonds may be weakened due to this ionisation. He developed simplified  DFT (sDFT) methods that can be applied to molecular dynamics, and assembled a “black box” which predicts the expected fragmentations over a time scale of a ps or so. By sampling the trajectories, he estimated the intensities of the various positively charged species and overlaid this on the observed EI-MS. The agreement was often spectacular. A particularly interesting example was the fragmentation of taxol. Here, no molecular ion is found, only much lighter ions. The molecular dynamics shows that rather than consecutive single-bond fragmentations, you instead get multiple bonds more or less all fragmenting at the same time. Tougher was to reproduce rearrangements, such as the McLafferty. Here, the semi-empirical method OM2 was more successful. His work means you can just “dial-a-mass-spectrum” and he speculates whether getting a good fit with the observed spectrum could tell you subtle aspects of the gas-phase molecular species, what its tautomeric state might be or perhaps even its conformation. He also described large-scale (800+) atom simulations of electronic circular dichroism (ECD) spectra of organometallic systems. Octahedral complexes can be prepared in chiral form, and this theoretical ECD treatment allows determination of absolute configuration of these often non-crystalline systems. Here you often need to compute 1000 or more electronic states, and if you have ever tried such ECD simulations, you will know that this is a lot of states!

We had been expecting Stefan to talk about dispersion effects in molecules, another emerging theme. Instead lots of other people mentioned them. In my talk I showed how including a D3-dispersion correction could dramatically change the predicted enantioselectivity of a chiral aldol condensation.[1]

The above observations of course cannot be in the least representative; typical of a modern conference there are five parallel sessions and 400+ posters, and so it represents a highly personal and selective snapshot.

References

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    Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions.

    Sunday, April 22nd, 2012

    Astronomers who discover an asteroid get to name it, mathematicians have theorems named after them. Synthetic chemists get to name molecules (Hector’s base and Meldrum’s acid spring to mind) and reactions between them. What do computational chemists get to name? Transition states! One of the most famous of recent years is the Houk-List.

    In the last 12 years or so, the area of enantioselective organocatalysis has blossomed, and an important example involves the asymmetric amino acid (S)-proline (below, shown in green). As its enamine derivative (below, shown in blue), it can catalyse the aldol condensation with an aldehyde or ketone to form two new adjacent stereogenic centres resulting from C-C bond formation (shown below as (R) and (S) as attached to the carbons connected to the red bond).

    The Houk-List transition state was located for this reaction, and as a useful model for rationalising the stereospecificity of this reaction it has become justly famous (although to be fair, other models have also been proposed). The challenge is to identify the factors selecting for just one stereoisomer (S,R in this case) over the other three (a similar challenge is described in this post for the heterotactic polymerisation of lactide). Houk, List and co-workers constructed their model (the example shown below is for R=isopropyl)  as follows.

    1. They employed a B3LYP/6-31G(d) density functional model.
    2. The geometry of the transition state was located for all four diastereomeric transition states using this method. Importantly, this geometry was for the gas phase, which provided a value for ΔG298†.
    3. These free energies were then corrected for the (relative) solvation energies of the four transition states. This was essential, since in the mechanism shown above, a neutral reactant gives a zwitterionic product, via a partially ionic transition state (indeed, the dipole moment of these transition states is around 10D). 
    4. The resultant Houk-List model then predicted that of the four isomeric transition states, the lowest was (as shown above) the (S,R) diastereomer.
    5. This particular transition state geometry has an interesting feature involving a 9-membered ring, large enough to accommodate a linear proton transfer without strain, by virtue of a trans double bond motif (the C=N bond). The (S,S) and (R,S) isomers have a cis motif instead at this location.

      Houk-List transition state. Original geometry.

    Well, this transition state is now nine years old. Unlike asteroids, or mathematical theorems, or indeed molecules and their reactions, a transition state is a slightly more ephemeral object. Its features and properties do rather depend on the particular quantum model used to construct it. There is one feature of the model, necessary in 2003, but no longer so in 2012. This was the use of a gas-phase optimised geometry, augmented at that geometry with a so-called single-point solvation energy correction. Nowadays, the solvation correction is included in the energy used in the geometry optimisation, which now properly reflects the effect of the solvation. Re-optimisation with this inclusion, at the ωB97XD/6-311G(d,p)/SCRF=dmso level thus updates the original Houk-List geometry.

    (S,R) Houk-List transition state, updated geometry. Click for 3D

    1. The most significant changes involve the O…H—O bond lengths. Respectively 1.13/1.31Å in the original, they change to 1.06/1.40Å at the new level.
    2. The forming C-C bond changes in length from 1.89 to 2.05Å (the latter, it has to be said, being a much more “normal” value for a transition state). 
    3. Whilst these might not seem very great changes, we do not yet know how they might impact upon the relative free energies of the four transition states. Houk and List reported the (S,R), (R,R), (S,S) and (R,S) relative free energies as 0.0, 6.7, 7.8 and 4.6 kcal/mol. The updated values for (S,R), (R,R), (S,S) and (R,S) [click on preceding links to view models] are 0.0, 6.0, 5.7 and 5.4 kcal/mol [click on preceding links to view calculation archives], which represent only minor changes to these energies.
    4. The (S,S) diastereoisomer is an interesting outlier. The transition state normal mode wave numbers are -373, -481, -815 and -402 cm-1 respectively and the O…H…O bond lengths for (S,S) are 1.18 and 1.20Å, a rather more symmetrical proton transfer than the other three.

    Which brings us to the main point; what is the origin of the diastereoselectivity? An NBO analysis can compare the total steric exchange energy (due to Pauli bond-bond repulsions) of the four isomers, which  turns out to be respectively 1214, 1221, 1235 and 1229 kcal/mol. In other words, the favoured isomer has the smallest steric exchange energy. Of course this one term is not the only contributing factor, and a more elaborate analysis will no doubt provide further insight.

    So an update to the Houk-List transition state reveals the general characteristics are intact and it is still a very useful model for analysing stereoselectivity in proline organocatalysis.

    Postscript:  The Intrinsic reaction coordinate  (for (S,S) ) is shown below.

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