Technique 8: Molecular Modelling.


  1. Objectives
  2. Chemical Modelling Projects
  3. Detailed Program System Instructions


  1. To become familiar with some common techniques for molecular modelling, via "real" chemical examples
  2. To use molecular mechanics to predict the geometry and regioselectivity of the hydrogenation of cyclopentadiene dimer, the stereochemistry of nucleophilic addition of a Grignard reagent and the conformation of a large ring ketone intermediate to the anti-cancer drug Taxol, via a choice of two programs (Chem3D) (< 3 hours)
  3. To use molecular mechanics to investigate Bredt's rule for Bridgehead alkenes as a function of ring size using Chem3D. To experience the skills involved in distinguishing between local and global minima. (< 4 hours)
  4. To use semi-empirical molecular orbital theory to investigate the regiospecificity of the electrophilic functionalisation of a bicyclic diene using Chem3D (< 2 hours).
  5. To use ab initio molecular orbital theory to investigate the frontier orbitals (and optionally the transition states) involving reaction of a highly strained bridgehead alkene, using an ab initio/density functional programs (Gaussian03) (< 3 hours).
  6. To use density functional molecular orbital theory to predict the 13C of your structure for your unknown compound (< 4 hours)
  7. To perform searches of the literature in order to cite in your final report any relevant references to each experiment as appropriate.

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Molecular Mechanics Modelling


A general introduction to the Molecular Mechanics (MM) method can be seen here. The present techniques illustrate several more complex applications of this method to typical chemical problems and the type of information that such modelling is capable of providing. This involves optimising molecular geometry to an energy minimum and analysing the final energy in terms of bond length and angle strain, steric effects and van der Waals contributions.


Before discussing specific applications of such a model, it is worth noting some of the limitations of the molecular mechanics approach. It is essentially a parametric method, using data from experimentally well characterised and known molecules. It is therefore used as an interpolative rather than an extrapolative technique, which cannot stray too far from "known chemistry". Thus it is not easily possible to model "kinetic control" of a reaction using the standard approach, since that requires knowledge of the transition state structure and energy. For the same reason, new molecules with unusual bonding are rarely amenable to modelling, and recourse has to be sought in the full quantum mechanical treatment of the system. Similarly, for molecular properties such as stereoelectronic effects, aromaticity, hyperconjugation and frontier orbital interactions which require a knowledge of the electron distribution within the molecule, recourse has to be made to quantum mechanical methods such as molecular orbital theory. Finally, molecular mechanics parameters are available only for certain types of bonds, and frequently are not available for many functional groups. Metal ions are also a category less easily handled at present by this type of model.

You will be using the Allinger MM2 or MM3 molecular mechanics models1 together with Chem3D. MM2 and MM3 are particularly appropriate for hydrocarbons.

Information Produced by the Programs.

Chem3D produces an energy (in kcal mol-1) together with optimised values for bond lengths, angles etc. This energy is a rather odd quantity. It is NOT related to any thermodynamic quantity such as ΔH, and energies obtained using two different force fields CANNOT be compared. You CAN however compare two energies calculated using the same force field for two different ISOMERS. You can also calculate energy differences for simple reactions such as the hydrogenation of alkenes, particularly if this is compared across a series of related reactions. The energy itself can be dissected into contributions from the stretching (str), bending (bnd), torsion (tor), van der Waals (vdw) and hydrogen bonding (H-Bond) energy terms. Each term indicates the deviation from "normality" of the particular function. For example, a very positive stretch term would indicate the predicted bonds are far from the "natural" lengths, due to some geometrical feature of the molecule. Comparing these terms across say two isomers provides a natural explanation for why one isomer may be more stable than the other.
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The Hydrogenation of Cyclopentadiene Dimer

Cyclopentadiene dimerises to produce specifically the endo dimer 2 rather than the exo dimer 1. Hydrogenation of this dimer proceeds to give initially one of the dihydro derivatives 3 or 4. Only after prolonged hydrogenation is the tetrahydro derivative formed. The modelling technique here involves calculation of the geometries and energies of all four species 1-4.

The relative stabilities of the pairs of compounds 1/2 and 3/4 should indicate which of each pair is the less strained and/or hindered in a thermodynamic sense. The observed reactivity towards cyclodimerisation and hydrogenation can of course be due to either thermodynamic (ie product stability) or kinetic (ie transition state stability) factors. In pericyclic reactions in particular, regio and/or stereoselectivity is controlled by the electronic properties of the molecules (stereoelectronic control), and hence can only be understood in terms of eg the molecular wavefunction (cf 2nd year lectures on pericyclic reactions). On the basis of the results obtained from the molecular mechanics technique you should be able to suggest whether the cyclodimerisation of cyclopentadiene and the hydrogenation of the dimer is kinetically or thermodynamically controlled.


Using Chem3D, define the two products 1 and 2 and optimise their geometries using the MM2 force field option. In the light of the above discussion, relate your results to the observed mode of dimerisation. The two products of hydrogenation 3 and 4 can be similarly compared so that a thermodynamic prediction of the relative ease of hydrogenation of each of the double bonds in 2 can be obtained. Analyse the relative contributions from the stretching (str), bending (bnd),torsion (tor), van der Waals (vdw) and hydrogen bonding (H-Bond) energy terms in terms of the relative stability of 3 and 4.
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Stereochemistry of Nucleophilic addition of a Grignard Reagent.

The optically active derivative of prolinol (5) shown below reacts with methyl magnesium iodide to alkylate the pyridine ring in the 4-position, with the absolute stereochemistry shown in 6.

Another recent example of this type of stereocontrol is shown below.

This reagent acts to transfer the NHPh group back to e.g. esters etc in a reverse of the reaction by which it was formed. On the basis of your previous calculations, can you speculate on the origin of the stereocontrol in the formation of this reagent? This reaction, by the way, links into the theme of atropisomerism discussed in the section on Taxol below, as a reagent for generating amides exhibiting (modest) atropenantioselectivity (a phenomenon induced by steric inhibition of rotation).


Use Chem3D to construct a model of the reactant, using the template option to introduce the proline sub-structure (do NOT include the MeMgI component. If you do try, what happens?). Minimise the model using the MM2 force field (Chem3D offers no option). Focus particularly on the geometry of the carbonyl group, and its (quantitative) orientation with respect to the aromatic ring. The "energies" of the molecules are much less important in this context. Discuss the geometry obtained in terms of the mechanism of reaction and in particular why the methyl group is delivered with the stereochemistry shown above. How can this simple model be improved (ie what is missing from the present model?).


  1. A. G. Shultz, L. Flood and J. P. Springer, J. Org. Chemistry, 1986, 51, 838. DOI:
  2. Leleu, Stephane; Papamicael, Cyril; Marsais, Francis; Dupas, Georges; Levacher, Vincent. Tetrahedron: Asymmetry, 2004, 15, 3919-3928. DOI: 10.1016/j.tetasy.2004.11.004

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Test of Bredt's Rule For Bridgehead Hydrocarbons.

A number of years ago, Bredt noticed that in compounds containing two or more fused rings systems, isomers containing a double bond at the bridgehead position tended not to form.

Subsequently, a number of such alkenes have indeed been prepared, and the double bond has been found to be highly reactive3. Since the molecular mechanics approach is capable of calculating ring strain quite accurately, it should in principle be possible to formulate rules for the stability and reactivity of bridgehead hydrocarbons based on such calculations alone. Any rule must be formulated by comparing several structures in a relative sense. There are at least two possible approaches to doing this.

  1. One can calculate the heat of hydrogenation of a series of bicyclic hydrocarbons as a function of ring size, and compare the values obtained with eg cyclohexane as a typical unstrained system.
  2. One can compare the calculated energies of the two double bond isomers of the bicyclic hydrocarbon in which the double bond is either at the bridgehead position or located away from it.


Devise a maximum of four bridgehead bicyclic alkenes which vary in ring size in some systematic manner. Using the Chem3D program and the MM2 force field, calculate the heat of hydrogenation of all four compounds, and compare graphically the results with eg the heat of hydrogenation of cyclohexene. Is it possible to devise a hydrocarbon which is more difficult (thermodynamically) to hydrogenate than cyclohexene ? (Hint: see ref 2). If it is possible in your examples to produce double bond isomers where the unsaturation is not at the bridgehead, attempt to see if there is a correlation between the isomerisation energy and the heat of hydrogenation. Discuss your conclusions in the laboratory report.


1. Molecular Mechanics: E. Eliel and N. L. Allinger, "Topics in Stereochemistry", Wiley, 1978.

2. W. F. Maier and P. von R. Schleyer, J. Am. Chem. Soc., 1981, 103, 1891. DOI: 10.1021/ja00398a003

3. G. A. Kraus, Y.-S Hon, P. J. Thomas, S. Laramay, S. Liras and J. Hanson, Chem. Rev., 1989, 1591. DOI: 10.1021/cr00097a013

4. I. Novak, J. Chem. Inf. Model., 2005, 45, 334-8. DOI: 10.1021/ci0497354.

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Stereochemistry and Reactivity of an Intermediate in the Synthesis of Taxol.

A key intermediate 10 or 11 in the total synthesis of Taxol (an important drug in the treatment of ovarian cancers) proposed by Paquette is initially synthesised with the carbonyl group pointing either up or down. On standing, the compound apparently isomerises to the alternative carbonyl isomer. This is an example of atropisomerism". Clearly the stereochemistry of carbonyl addition depends on which isomer is the most stable. It is also noted that during subsequent functionalisation of the alkene, this reacted abnormally slowly!


Using molecular mechanics (MM2) to determine the most stable isomer 10 or 11, and to rationalise why the alkene reacts slowly (hint: see previous exercise!). Pay particular attention to the conformation of the resulting optimised structure, to see if any aspect of this structure could be improved by further minimisations (preceeded if necessary by a manual edit of the structure to move atoms into more correct orientations).

  1. S. W. Elmore and L. Paquette, Tetrahedron Letters, 1991, 319; DOI: 10.1016/S0040-4039(00)92617-0
  2. See J. G. Vinter and H. M. R. Hoffman, J. Am. Chem. Soc., 1974, 96, 5466 (DOI: 10.1021/ja00824a025) and 95, 3051 for another nice example of atropisomerism.
  3. Another well known example is within Vancomycin: J. Am. Chem. Soc., 1999, 121, 3226. DOI: 10.1021/ja990189i
  4. An interesting variation is of "atropenantioselective cycloetherification" (G.ÊIslas-Gonzalez, M.ÊBois-Choussy and J.ÊZhu, Org. Biomol. Chem., 2003, 30-32. DOI: 10.1039/b208905. See also Leleu, Stephane; Papamicael, Cyril; Marsais, Francis; Dupas, Georges; Levacher, Vincent. Tetrahedron: Asymmetry, 2004, 15, 3919-3928. DOI: 10.1016/j.tetasy.2004.11.004

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Modelling Using Molecular Orbital Theory.


In part 1, the strengths and weaknesses of a purely mechanical molecular model were illustrated. In particular, the endo stereoselectivity in Diels Alder cycloadditions was attributed to "secondary orbital" interactions, which the Molecular Mechanics approach cannot handle. In this section, several such electronic aspects of reactivity will be illustrated, showing how explicit consideration of the electrons in molecules must be taken into account.

Regioselective Addition of Dichlorocarbene

Orbital control of reactivity is illustrated in the reaction of compound 12 with electrophilic reagents such as dichlorocarbene or peracid;

In modelling such a reaction, we require a program where the geometry of 12 can be predicted, and the energy of the orbitals calculated and their form displayed graphically. Use the Chem3D program and select the PM3 valence-electron self-consistent-field MO method to provide an accurate representation of the valence-electron molecular wavefunction, and in particular of the HOMO (Highest Occupied Molecular Orbital), presumed to be the most reactive towards electrophilic attack.
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Using the Chem3D program, draw the molecule, and select Calculations/MOPAC/Minimise energy option from the top menus, and from the Theory pane, select PM3. [It might be advantageous for you to process the drawn molecule first using Mechanics to tidy it up a bit, and only then to subject it to MOPAC]. When this is complete, select Gaussian/Compute Properties and Molecular Surfaces. When complete (about 4 minutes), select View/ Molecular orbitals. The HOMO appears by default. Select View/Select molecular orbital to view the HOMO-1, the LUMO, LUMO+1 and LUMO+2. Copy (as bitmap) and paste each orbital into Word.


1. T. L Gilchrist and R. C. Storr, Organic Reactions and Orbital Symmetry, CUP, 1979.

2. B. Halton, R. Boese and H. S. Rzepa., J. Chem. Soc., Perkin Trans 2, 1992, 447. DOI: 10.1039/P29920000447

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Reactivity of Diels Alder Reactions

The different reactivity of 13 and 14 can also be explained by the energies of the frontier orbitals, or more accurately by the barriers to the transition states for the reactions.

The energy of the HOMO will be calculated for both systems. The one with the highest energy HOMO (least negative) is the one likely to react fastest. In this case, you will calculate the HOMO energies of 13 and 14 using Gaussian, which allow "ab initio" wavefunctions to be calculated and displayed (the calculation is performed without the butadiene, which is common to both and hence is neglected).


You can use the Chem3D, Gaussview programs or the brand new SCAN to run a Gaussian calculation. Select Gaussian/Minimise Energy from the top level menu, and in the Theory section, specify Method: DFT=B3LYP (Density functional theory), Wavefunction= Restricted Closed Shell and 6-31G Basis set with Polarisation set to d. (or if you are in a rush, use the much faster 3-21G basis set). HINT 1: Pre-optimise the structure using a fast method such as Molecular mechanics, before submitting the ab initio calculation. If you do not do this, the latter will take much longer! HINT2: Inspect your geometry for 14 carefully; it is possible to get an unexpected (high energy) stereoisomer. Think about it!

Using the SCAN. The SCAN is: SuperComputer-At-Night. With this, you can run larger molecules, or smaller molecules at a much higher level of theory. Proceed as follows:

  1. Using the Chem3D or Gaussview programs to create a Gaussian input file (a .gjf file).
  2. Go to and log in.
  3. Select Projects and create a project name suitable for your needs.
  4. Select New Job, Chemistry Condor Pool, your project, the.gjf file created earlier, and click on submit. The Job will run overnight and can be collected from this web page. In particular, if you select the Formatted checkpoint file from output list, and download it, Gaussview will open it and display the result of your calculation. You can also open this file with Chem3D.
  5. The SCAN is powerful enough that if you wished, all the molecules in this technique could be submitted using the Gaussian program. You can submit multiple jobs, one after another using this technique. You could also increase the level of theory. In this case, change the basis set from 6-31G(d) to e.g. cc-pVTZ, or you could e.g. Include vibrational analysis, which in fact will result in an entropy correction to the energy, to give in effect a ΔG for your energy.


  1. H. O. House, J. L. Haack, W. C. McDaniel, and D. VanDerveer, Enones with strained double bonds. 8. The bicyclo[3.2.1]octane system, J. Org. Chem., 1983, 1643-1654. DOI: 10.1021/jo00158a014

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Predicting the 13C Spectrum of your unknown compound

The 13C spectrum of an organic molecule can be predicted using two quite different methods.

  1. The first is a rule-based approach derived from a fragment library; the MestreNova program uses this method. The advantage is that the prediction is extremely rapid, and fairly general. The downside is that the accuracy is only around 3-5 ppm, and does not take into account local conformations, differential solvation of different groups, etc etc. If you want to try this approach, some concise instructions are to be found here.
  2. The second is the so-called GIAO approach using quantum mechanical density functional theory. The background to this, and a famous recent example can be found in the article by Rychnovsky1 on a revision of the structure of Hexacyclinol. He reports that the mean error for the 23 carbon shifts in the predicted structure was around ± 1.8 ppm, with a maximum error of around 5.8 ppm. An improved procedure which reduces the mean and maximum errors by one half will be used here2, although a number of caveats for successful prediction should be noted. The most serious is that the method is highly sensitive to the conformation of the molecule. If various different conformations are possible (and for some molecules, 100s of reasonable conformations can sometimes be imagined), they should all be scanned by this method. Since this is clearly not feasible in a reasonable time, you should not expect a fit to your unknown compound to be as successful as the preceeding errors might suggest.
  3. Important: Experiment 8 is designed teach how how to evaluate an unknown compound by predicted its NMR chemical shifts. Your unknown compound is a useful example to use, but you will not be graded here on whether you have correctly identified it or not. If you do not yet know the identity of the molecule, then attempt a reasonable guess. If that guess is not correct, you will NOT be penalised at all during the marking of expt 8.


You will need to sketch your molecule in ChemDraw Pro/Chem3D and perform an initial refinement of its 3D geometry. If it contains only simple elements (CHNO, Si, P, S, halogens) then the chances are that a molecular mechanics refinement will be possible. At this stage, whilst the calculations still take only a few seconds, you might wish to investigate several conformational possibilities to see which might be the lowest (but don't try more than say 5). Some conformations can be preset (a worthwhile one is to always try to get 6-membered rings into a chair, and e.g. esters R-CO-O-R' oriented such that the R-C bond is antiperiplanar to the O-R' bond). If the mechanics procedure fails because of lack of parameters, try eg the MOPAC/AM1 approach instead. If both of these fail, try the Gaussian procedure, using the HF (Hartree-Fock) method and an STO-3G basis set. This initial geometry will then have to be refined/optimized using the following method.

  1. In Chem3D, go to Calculations/Gaussian/Create Input File.
  2. Select Job Type/Minimise; Method DFT=mpw1pw91
  3. Save the resulting file to your H: drive, making sure it is saved as a Gaussian Input file, with the suffix .gjf.
  4. Find the file in Windows Explorer, and with a right-mouse-click, open it with the WordPad program.
  5. Delete all lines at the top, leaving only the following line, which should be edited to show:
    # mpw1pw91/6-31(d,p) opt(maxcycles=15) scf(conver=7)
    NMR calculation for unknown compound
    0 1
    C  0  -4.35079359    2.69494079   -2.13433575
     ... ... ...
    This shows the keyword line at the top, a blank line, a title card, another blank line, a charge/spin card (we will assume that your unknown is neutral and a singlet spin state) and the first line of atom coordinates. Re-save this file, making sure you save it as TEXT and NOT RTF and that it retains the suffix .gjf.
  6. Go to, log in, and first create a project (it could simply be called unknown compound). Then, New Job/Chemistry Condor Pool, then select Gaussian/Your project, and finally the name of the Gaussian input file you have just saved, along with a descriptive title.
  7. You can view your job list, when a display of the type shown below should appear:

    Jobs in the pool tend to run overnight, and you will probably have to wait till the next day for the job to complete. The status of the pool can be inspected by selecting Pools from the menu on the left:

    If your suspected molecule is large (more than about 22 non-hydrogen atoms) it may require more powerful computer facilities. If the job returns no output overnight, it may well have run out of time (it has about 9 hours in which to complete the calculation). You could run on a faster computer; contact Prof Rzepa in this case.
  8. When the job shows as Finished, select the Gaussian Checkpoint file as the required output:

    and download it (probably to the desktop, or wherever the browser tells you). Double-click the file to open Gaussview (it may happen automatically) and check that the optimised geometry is still reasonable. Invoke File/Save as and replace the original Gaussian input file you created with Chem3D. It now has a fully optimised geometry, rather than the initial sketch of before.
  9. If the system responds that the formatted checkpoint file does not exist its quite probable that the calculation failed. Two common reasons for the failure are
    1. There was an error in the input .gjf file. A common error is the positioning or omission of blank lines. Check with the above to ensure they are correctly positioned. Another error is that the keywords are mis-typed.
    2. The calculation may have run for 9 hours and then run out of time (see above)
  10. Repeat the Wordpad editing procedure as described above, but this time ensure the top line contains the following
    # mpw1pw91/6-31(d,p) NMR scrf(cpcm,solvent=chloroform)
    NMR calculation for unknown compound
    0 1
     Br   0  -4.37079359    2.59494079   -2.03433575
  11. Resubmit this new input file for calculation as described above. This will take less time to calculate than before.
  12. When this second calculation is finished, download this time the Gaussian Log file (instead of the checkpoint file). Open this in Gaussview and from that program, select Results/NMR (if the NMR keyword is greyed out, it means the calculations was not in fact successful).
  13. From the Spectral display that appears, select the C nucleus, and the appropriate Reference Value:

    click on any peak to find out what its chemical shift is, and compare with the spectrum that you have been issued with.
  14. You should note that carbons attached to "heavy" elements (particularly eg halogens) have shifts which need correction for so-called Spin-orbit coupling errors. Typically, C-Cl needs correcting by -3 ppm, C-Br by -12 ppm, and C-I by about -28 ppm. Other elements to be determined!2. Another systematic error present is that the carbonyl of esters, amides etc tends to be out by about 5ppm. Use the following simple correction for such carbons only: δcorr = 0.96δcalc + 12.2.
  15. You can probably use your calculation to actually assign the 13C shifts to the carbons of your molecule. If you spot one or more carbons out by more than about 5ppm, its quite likely that you have the wrong conformation of your molecule in that region (i.e. the method can actually be used for conformational analysis).
  16. The method should work for other nuclei (except hydrogen, which requires much greater accuracies to be really useful).
  17. Complete this section by returning to and click on the publish link next to the job that carries the NMR prediction. This will deposit your calculation into a so-called Digital repository, from whence it can be retrieved by anyone wishing to find it. In this instance, it could be checked during the process of grading your final report.


  1. S. D. Rychnovsky, Org. Lett.,, 2006, 13, 2895-2898. DOI: 10.1021/ol0611346
  2. C. Braddock and H. S. Rzepa, J. Nat. Prod., 2007, submitted for publication.

Predicting the 3J H-H couplings of your unknown compound

The above technique is reliable for 13 shifts, but less so for 1H shifts. However, three-bond couplings can be predicted reasonably well using a very rapid and simple method. To to this, you will need to have a 3D model of your unknown, which should emerge out of your 13C prediction in the preceeding section. The start point should be to use Chem3D to save an MDL Molfile of your final coordinates. This can then be read into Janocchio, to provide the coupling constants.

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Report Preparation

In your report you should discuss your evaluation of each of the techniques you use here. You should include at least three literature references in addition to the ones given here.

The simplest way of producing a report of these experiments is to select and copy diagrams from Chem3D software to an Office 2003/2007 document. Please save as a .doc document rather than the default .docx format. Submit by email to

Important: We have had, in the past, instances of students copying another's molecule and orbital diagrams and submitting these in their report. This is considered plagiarism, and if detected will result in disciplinary proceedings. If your diagrams for some reason are lost due to computer failure, please discuss this with the demonstrator.

Copyright (c) H. S. Rzepa and Imperial College London Chemistry Department, 1994-2007.