Coursework

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Molecular modelling Coursework to be attempted during Scheduled Sessions

These projects are arranged in increasing order of difficulty, and time taken to complete. You should do as many as you can in the three-hour session allocated to you, and return to finish the rest if you wish at your convenience. At the end of each session, we will conduct a number auction. For each project, the bidding will start with the first volunteer offering an energy for the system (or one of the isomers). If anyone has a lower energy for that molecule, they will then bid that energy. The winner will be the one with the lowest energy. All of these projects should be attempted using the MMFF94s force field in Avogadro in order that energies are being compared like with like. An introduction to the features and usage of Avogadro may be found here

Conformational analysis I: Chair and Boat conformations of Cyclohexane

Cyclohexane

Construct chair-like and boat-like conformations of cyclohexane. Compare the energies of both forms. Check carefully the geometry of the boat; does it have any unusual feature?

Chiralane

Optional: Try changing one or more of the CH2 groups into an oxygen and see if that affects things. Optional: The molecule on the left is called chiralane. Are its rings boats or chairs?

References and further exploration

1. The first suggestion of two forms for cyclohexane goes as far back as H. Sachse, Chem. Ber, 1890, 23, 1363 and Z. Physik. Chem., 1892, 10, 203. This is nicely explained here. E. Mohr, J. Prakt. Chem., 1918, 98, 315 and Chem. Ber., 1922, 55, 230, translated Sachse's argument into a pictorial one.
2. The article that put conformational analysis on the map: D. H. R. Barton and R. C. Cookson, The principles of conformational analysis, Q. Rev. Chem. Soc., 1956, 10, 44. DOI:10.1039/QR9561000044
3. Wikipedia article
4. D. A. Dixon and A. Komornicki, Ab initio conformational analysis of cyclohexane, J. Phys. Chem., 1990, 94, 5630 - 5636; DOI:10.1021/j100377a041 .
5. For a more modern application of this technique, see I. Columbus, R. E. Hoffman, and S. E. Biali, Stereochemistry and Conformational Anomalies of 1,2,3- and 1,2,3,4-Polycyclohexylcyclohexanes. J. Am. Chem. Soc., 1996, 118, 6890 - 6896; DOI:10.1021/ja960380h .
6. Animations of the interconversion process can be seen at this blog: http://www.ch.imperial.ac.uk/rzepa/blog/?p=7926
7. For the record, the point group symmetries of the various species which may be involved are D_3d for the chair conformation, C_2v for a boat geometry, and D₂ for any twisted boat form. Is any of these forms chiral?
8. The second molecule shown in this section is called [6.6]chiralane. It is peculiar for having many six-membered saturated rings, all of them as twist-boats rather than chairs! (a chair has a plane of symmetry, a twist boat only axes, which of course allows it to be chiral). See here for more details.
9. More detail on the conformation of rings (and acyclic systems) will be found in the lecture course on the topic to be given in the spring term.

Enantiomers vs Diastereomers Part 1: Butanes

This problem illustrates, using models, the difference between an enantiomer and a diastereomer.

2-chloro-3-bromobutane

2-bromo-3-chlorobutane The compound 2-bromo-3-chlorobutane has two chiral centres, and four isomers (22) are therefore possible. Calculate all four isomers, and for each be careful to label each of the two stereo centres R or S as you go. For each of the four isomers R,R, S,S, R,S, S,R you will have to think about whether you have obtained the lowest energy conformer. (The feature Build > Invert Chirality in Avogadro may come in useful) Can your four energies be grouped in any sensible way? Another example of relevance to the problem sheets associated with the lecture course is shown on the right. Can you use modelling to predict the relative energies of the four possible diastereoisomers resulting from formation of the aldol product? You will have to consider the conformations of your stereoisomers, and whether there are any other factors which may intervene in stabilising one stereoisomer over the other?

A reality check: A search of the Cambridge database

search query

To find out what the optimal conformation of a 2,3-dihalobutane actually is (in the solid state), we can search for this in the Cambridge database. The search query needed is shown on the right and will be demonstrated in the lab. The outcome is shown on the left.

References and further exploration

1. Wikipedia article on Diastereomers
2. The Cahn-Ingold-Prelog Priority rules

Enantiomers vs Diastereomers Part 2: Helicenes

Pentahelicene

Circulene Circulene Circulene

Construct some helicenes (pentahelicene or [5]helicene is shown on the right), using conjugated bonds for all the ring bonds. Benzene, naphthalene, phenanthrene and benzophenanthrene are in fact the first four members of this series. At what point in this series can you detect helicity cropping up? This is manifested by a non-planar helical wind of the molecule. If you do detect it, note how the wind is either left or right handed, ie the two forms are enantiomers of each other. Try displaying the molecule in spacefill mode (select 'Van der Waals spheres' under Display Types, or if you're feeling adventurous go Extensions > Create Surfaces...) to see if you can identify the source of the helicity. Optional: [7]circulene is a known molecule shown on the left. Is it flat? (see DOI:10.1021/ja00219a036 ). An [8]circulene is also known (DOI:10.1021/jp806134u ) [5]circulene has instead a five-membered central ring. It too is puckered, but not nearly so much as [7]circulene. See DOI:10.1021/ja306992k These are all related to graphene (Nobel Prize 2010).

References and further exploration

1. Wikipedia article on Helicenes and related molecules
2. The higher helicenes are well known (up to about [14]helicene) and amongst the most chiral molecules known (in terms of how much they rotate the plane of polarised light).
3. The smallest helicene which can be resolved experimentally into enantiomers is in fact [5]helicene].
4. R. H. Janke, G. Haufe, E.-U. Würthwein, and J. H. Borkent, Racemization Barriers of Helicenes: A Computational Study, J. Am. Chem. Soc., 1996, 118 6031 - 6035 DOI:10.1021/ja950774t

Conformational analysis II: cis and trans-decalins

Cis decalin Elimination Woodward

cis Decalin This is the famous molecule that started the whole molecular mechanics modelling ball rolling. Barton in 1948 sought to find out which conformation of cis-decalin was the most stable (see here for video). You should be able to find at least three conformations of this molecule. Try locating these, and conclude which is the most stable. Identify any chair rings and any boat. It took Barton months using a hand-cranked calculator to evaluate the relative energies of the various conformations. You will do it in seconds. Measure some dihedral angles (select the Measure tool and click on the four atoms between which you wish to measure. Angles and distances will appear in the bottom left) to see if the staggered relationships hold (i.e. for such a relationship, the dihedral angle should be close to 60 degrees). Optional: A key step in Woodward's famous synthesis of cortisone is a quinone+butadiene Diels-Alder reaction to give a cis-decalin (left), with an assumption that epimerisation to a trans-decalin is thermodynamically favourable. cis Cortisone Can you verify whether the trans-isomer is indeed more stable? Its not so obvious, since this compound has two extra double bonds in the rings and six sp2 centres which might perturb things. trans Decalin Optional: The two diastereomeric trans-decalin tosylates react quite differently with NaBH4. Construct models for both isomers (use methoxy as a model for the Tosyl group) and from the antiperiplanar alignments of bonds that you can find in each isomer, can you make a connection to the reactivity of each form? Consider very carefully where you would put a lone pair located on the nitrogen (i.e. include the N-Lp "bond" in your antiperiplanar alignments) asuming the this atom is tetrahedral rather than planar. Does this lone pair play any part in either reaction in this position?. Note that the relative energy of the axial/equatorial N-Methyl group will not be an accurate reflection of any antiperiplanar alignments, since these are predominantly electronic in origin, and this mechanics method does not take these into account. The second (elimination) reaction is very slow compared to the first. Discuss with tutors why this might be so (for Hints, see here or here). These reactions do not appear to occur for the corresponding cis-decalins6. Why not?

References and Footnotes

2. Wikipedia article
3. For a modern application of mechanics to this molecule, see J. M. A. Baas, B. Van de Graaf, D. Tavernier, and P. Vanhee, Empirical force field calculations. 10. Conformational analysis of cis-decalin, J. Am. Chem. Soc., 1981, 103, 5014 - 5021; DOI:10.1021/ja00407a007 .
4. For a video-Podcast of Barton and Woodward (and other Nobel prize winners), subscribe here
5. R. B. Woodward, F. Sondheimer, and D. Taub, The total Synthesis of Cortisone, J. Am. Chem. Soc., 1951, 73, 4057 - 4057. DOI:10.1021/ja01152a551 .
6. P.-W. Phuan and M. C. Kozlowski, Control of the Conformational Equilibria in Aza-cis-Decalins: Structural Modification, Solvation, and Metal Chelation, J. Org. Chem., 2002, 67, 6339 - 6346; DOI:10.1021/jo025544t

Enantiomers vs Diastereomers Part 3: Stereochemistry of conjugate addition

The reaction on the right is taken from a lecture problem sheet. Part of the problem involves assigning the stereochemistry of the methyl group.

1. Assuming that the reaction is thermodynamically controlled, which of the two possible diastereoisomers is lower in energy?
2. In fact, the reaction proceeds via a Cu-alkene π-complex and a more accurate model would involve computing the energy of that model rather than the product of the reaction as above. In general, the molecular mechanics method does not handle transition elements, and one would have to use quantum mechanics instead.
3. It may indeed be that it is the transition state for the reaction of the Cu complex that needs to be modelled, not the complex itself. This too is beyond the scope of the current lab.
4. A second example from the problem sheet is shown below the first. There are two regiochemical outcomes, each with an unknown stereochemistry for the methyl group. Does molecular mechanics modelling cast any light on the possible answers?
   • The difference in behaviour of Mg and Cu is again not something that mechanics can easily address. Here again, this aspect of the chemistry has to be tackled using an electronic theory of chemistry, not a mechanical one.

References

Menthone/isomenthone and Bridgehead enols: Thermodynamic vs Kinetic Control Part 1.

Menthone Menthone

Menthone Beckmann (of rearrangement fame) in 1889 dissolved optically active levorotatory (-) (S,R)-menthone ([α]D -28°) in conc. sulfuric acid, followed by quenching on ice to give what Beckmann assumed was pure (and what we would nowadays call diastereomeric) (+) (R,R)-isomenthone, [α]D +28°. He suggested for the first time that such an isomerisation, involving epimerisation at the asymmetric centre next to the keto group, proceeded via an intermediate enol in which the tetrahedral asymmetric carbon becomes planar. But this famous (perhaps even notorious2) early example of a reaction mechanism makes an interesting assumption, which can be tested by molecular modelling. Two possible enols can be formed, one of which is the so called thermodynamic enol, the other being the kinetic enol. Only one of these enols can resulting in the menthone isomerising to isomenthone. Find out if simple molecular modelling correctly predicts that the thermodynamic enol is indeed the more stable of the two. Hint: Model the enol and not the ketone. Consider carefully any conformational isomers possible. Given that the optical rotation3 of pure (+)-isomenthone is now known to be [α]D +101° rather than +28°, we can infer that Beckmann's product contains only 43% isomenthone and hence still contains 57% of original menthone, corresponding to an equilibrium constant of K= 0.75. This can be related to a (free energy) difference using the equation ΔG = -RT ln K, or ΔG = 0.7 kJ/mol (menthone being lower in energy by this amount compared to isomenthone). Can this energy difference be verified using molecular mechanics modelling? Can you explain why menthone is the more stable? (For another hint, or possibly a fright, visit this page). To study the kinetic process, we cannot use the Molecular mechanics approach, since we will need to find the transition state for proton removal. Mechanics by its nature cannot break bonds, and so the only vialble method is quantum mechanics, which you will encounter next year. Enols Optional: The molecule on the right is taken from Don Craig's problem sheet 1, associated with the lecture course on enols in synthesis. Four different hydrogens could potentially be removed by treating the compound with base. Construct the model, and from inspection, can you decide which of the four possible enols might form? Calculate the energies of all four. Which is lowest? (Hint: the carbanion orbital resulting from proton removal has to be able to conjugate with the π-system of the carbonyl group).

References and footnotes

1. E. Beckmann, Annalen, 1889, 250, 322. DOI:10.1002/jlac.18892500306 .
2. Many of Beckmann's misconceptions were corrected by O. Wallach, Annalen, 1893, 276, 296. DOI:10.1002/jlac.18932760306 . The notoriety is because the coincidence of equal but opposite optical rotations obtained in this experiment led Beckmann to believe that he had obtained the enantiomer of menthone, and not as we now know, the impure (R,R) diastereomer. It should be borne in mind that the concept of tetrahedral and asymmetric carbon was only 15 years old at this time (see Jacobus Henricus van't Hoff and Joseph Achille Le Bel). Nevertheless confusion over this aspect persisted for some time after, and was often evident in the writings of even very famous chemists of the time (and Beckmann was very famous!).
3. Wikipedia article
4. From about 1890-1935, mechanistic organic chemistry was born. In the absence of UV, IR, NMR, MS and X-Ray techniques, the polarimeter occupied a pivotal role. Many of the great discoveries in reaction mechanisms (keto-enol tautomerism as seen here, carbocations, the Walden inversion, etc) relied on polarimetric measurements.
5. A notorious modern example of (unwanted) epimerisation of a ketone is Thalidomide, where one epimer inhibits morning sickness in pregnant women, and the other epimer is teratogenic, causing fetal abnormalities. The equilibrium in this case does not require conc. sulfuric acid, but can occur at physiological pH.

Inorganic Conformational Analysis: Symmetry in Crystal versus Solution phase

One of the advantages of Avogadro is its inclusion of the Universal Force Field, allowing for modelling of non pharmaceutical molecules, so to speak. In this exercise you will be able to compare a recorded crystal structure of an 8 membered siloxane ring (You may remember making a similar compound in your first year, indeed your correspondent certainly does...) to its UFF optimised structure.

An 8 membered siloxane

1. To begin with, find the lowest energy conformation of ((CH₃)₂SiO)₄ (consider the relative directions the oxygen atoms protrude from the ring) and whether it is of higher or lower symmetry than the next lowest energy conformation.
2. Download the Crystallographic Interchange file File:BAPRIU.cif associated with the spirocyclic compound {[(CH₂)₂N₂(tBu)₂]SiO(Cl)₂SiO}₂ and open with Avogadro. WITHOUT optimising:
   1. Measure the dihedral angle between the four oxygen atoms and the four silicon atoms (select the Click to Measure tool [or press F12] and select them in order).
   2. Try and find the single C₂ axis this structure contains. (Middle clicking the mouse allows rotation about an axis perpendicular to the monitor - this may help some people visualise)
3. Without changing the positions of any atom, begin optimising with the universal force field (conjugate gradients algorithm):
   1. Compare dihedral angles within the ring and check to see if the C₂ axis still exists in this conformation (and are there any others?). Recall whether the purely methylated ring was in its lowest energy at the conformation presented or not.
4. Invert the configuration at any two of the nitrogens (ie such that the positions of the lone pair and the ^tBu swap over) and convince yourself that the resultant structure is chiral. Use Build > Invert Chirality to check.

References and Footnotes

Coursework not to be attempted at any time: Antimodelling Molecules

The following represent molecules that should not be modelled under any circumstances! You should instead attempt to NAME them.

If you know of any other antimodelling molecules, please add them here!

Acknowledgements

Some of these cartoons are from here, and six are original. A superb collection of silly names is maintained by Paul May . See DOI:10.1021/jo0349227 for the nanoputians. Music and Chemistry also go together.

Further examples (optional)

There are more examples here if you wish to try them in your own time.

Getting your own copy of the Avogadro program

The program is free and can be obtained here. Instructions for its use can be found here.

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