View source for Mod:further coursework

== Optional: Additional Molecular modelling Coursework  ==

Please feel free to try these problems in your own time, and to discuss these with your organic tutors and lecturers. Note also that the relevant lectures may occur in the spring as well as autumn terms.
=== Axial/Equatorial preferences in cyclohexane and cyclohexanone and Hydrogen Bonding ===
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#Construct a chair cyclohexane and replace firstly one of the [[axial]] hydrogens with  the following groups: '''methyl''', '''t-butyl''',  '''OH'''. Calculate the energy of the axial  isomer.  
# Then repeat (either by deleting/redrawing or by  moving) for the equatorial forms.  Compare the energies of the two isomers.  Does any energy difference increase with the size of the group?  Does  OH fit into this in  terms of size? 
# [[Image:Thiomethylcyclohexanone.gif|right|thumb|thiomethyl cyclohexanone]]The dissolving metal reduction of cyclohexanones  in  a protic solvent (i.e. one capable of hydrogen bonding) is thermodynamically controlled and gives the more stable, equatorial alcohol.  In fact, its probably the alkoxide that is the product, not the free alcohol.  It is thought the alkoxide is actually a lot larger than the alcohol, accounting for the substantial equatorial preference.  Can you think why its larger? [Ghemical cannot in fact model this, since the force field does not include parameters for the alkoxide anion].
# Determine the axial/equatorial preference of 2-methylthio-cyclohexanone (Hint: there are many conformations possible, and you should try a few to see if you can get the lowest).
|}
==== References and Footnotes ====

# A. H. Lewin and S. Winstein, ''NMR. Spectra and Conformational Analysis of 4-Alkylcyclohexanols'' ''J. Am. Chem. Soc.''; '''1962''', ''84'', 2464 - 2465; {{DOI|10.1021/ja00871a049}}
#F. R. Jensen and L. H. Gale, ''The Conformational Preference of the Bromo and Methyl Groups in Cyclohexane by IR Spectral Analysis'', ''J. Org. Chem.'', '''1960''',  ''25'',  2075 - 2078.  {{DOI|10.1021/jo01082a001}}
# K. B. Wiberg, J. D. Hammer, H. Castejon, W. F. Bailey, E. L. DeLeon, and R. M. Jarret, ''Conformational Studies in the Cyclohexane Series. 1. Experimental and Computational Investigation of Methyl, Ethyl, Isopropyl, and tert-Butylcyclohexanes'',  ''J. Org. Chem.'', '''1999''',  ''64'',  2085 - 2095; {{DOI|10.1021/jo990056f}}.  The salient point here is that the [[enthalpy]] and[[entropy]] of this series differ in their trends.
# Just when you are starting to think that things are quite simple, along comes the observation: S. E. Biali, ''Axial monoalkyl cyclohexanes'',  ''J. Org. Chem.'',  '''1992''',  ''57'',  2979 -2980; {{DOI|10.1021/jo00037a001}}
# And this one with  knobs on: ''In all-trans-1,2,3,4,5,6-hexaisopropylcyclohexane, all the alkyl groups are located at axial rather than equatorial positions:   O. Golan, Z. Goren, and S. E. Biali, ''Axial-equatorial stability reversal in all-trans-polyalkylcyclohexanes'', ''J. Am. Chem. Soc.'', '''1990''', ''112'', 9300 - 9307.   {{DOI|10.1021/ja00181a036}}.
#J. A. Anderson, K.  Crager, Kelly, L.Fedoroff, G. S.  Tschumper, Gregory S.  ''Anchoring the potential energy surface of the cyclic water trimer.'' ''J. Chem. Physics'',  '''2004''',  ''121'',  11023-11029. {{DOI|10.1063/1.1799931}}.
#R. R. Fraser, N. C. Faibish,  ''On the purported axial preference in 2-methylthio- and 2-methoxycyclohexanones: steric effects versus orbital interactions'', ''Can.  J.  Chem.'',  '''1995''',  ''73'',  88-94.
=== Conformational analysis II: ''cis'' and ''trans''-decalins ===
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# A key step in Woodward's famous synthesis of  [http://en.wikipedia.org/wiki/Cortisonecortisone] 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.[[Image:Cortisone.gif|thumb|right|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  sp<sup>2</sup> centres which might perturb things.  
#[[Image:App.gif|thumb|right|trans  Decalin]] The two diastereomeric ''trans''-decalin tosylates react quite differently with  NaBH<sub>4</sub>.  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 [[organic:entropy|here]] or [[organic:ngp|here]]).
#*These reactions do not appear to occur for the corresponding  ''cis''-decalins<sup>6</sup>.  Why not?
|}

==== References and Footnotes ====
<references/>
<ol start="2">
<li>[http://en.wikipedia.org/wiki/Decalin Wikipedia article]</li>
 <li>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}}.</li>
<li> For a video-Podcast of Barton and Woodward (and other  Nobel prize winners),  subscribe[http://www.ch.ic.ac.uk/video/index.rss here]</li>
<li> 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}}.</li>
<li> 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}}</li>
</ol>

===  Thermodynamic vs Kinetic Control Part 2.===

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#[[Image:Enols.jpg|thumb|right|Enols]] The molecule on the right has four different hydrogens that 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 &pi;-system of the carbonyl group).
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=== How to induce room temperature hydrolysis of a peptide ===
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[[Image:amide-cleavage.png|thumb|right|Peptide hydrolysis]]  This introduces a further example of how simple conformational analysis can quickly rationalize kinetic behaviour. At neutral  pH and 25&deg; the half life for hydrolysis of a peptide bond is around 500 years (and thank goodness, or we would ourselves all rapidly hydrolise to a mush!). Some enzymes however can achieve this in less than 1 second, an acceleration of 10<sup>13</sup>! Organic chemists are not quite so clever, but they can achieve room temperature hydrolysis of a peptide in 21 minutes by careful conformational design. The two isomers shown on the right differ only in their stereochemistry, one hydrolysing quickly, the other slowly.  Build a model of each compound, and calculate two isomers for each, varying in whether the ring N-substituent is oriented axial or equatorial with respect to the decalin ring. On the basis of  your two pairs of energies, can you rationalise the observed kinetic behaviour?  Do you know why both of these compounds take very much less than  500 years to hydrolise the peptide bond?

'''Hint1:''' Use the chair-chair conformation for cis-decalin as your template for constructing this system.

'''Hint2:''' When constructing your models, think if there are any hydrogen bonds that might stabilize the structure!

'''Hint3:''' Hydrolysis can only occur when the OH group can approach the carbonyl of the peptide bond close enough to react, and at the right angle of approach.
|}

==== Reference ====

# M. Fernandes, F. Fache, M. Rosen, P.-L. Nguyen, and D. E. Hansen, 'Rapid Cleavage of Unactivated, Unstrained Amide Bonds at Neutral pH',  ''J. Org. Chem.,'' '''2008''', ASAP:{{DOI|10.1021/jo800706y}}

=== Caryophyllene: The phenomenon of  Atropisomerism ===

# [[Image:caryophyllene-ketone.gif|thumb|right|Caryophyllene ketone]] [http://en.wikipedia.org/wiki/Caryophyllene Caryophyllene], a constituent of many essential oils, include clove oil, has a[[trans]] alkene contained in a 9-membered ring. One interesting property is that it has 4 [[diastereoisomers]] possible, originating from a total of three asymmetric centres present in the molecule. Two of these are conventional chiral centres, one is present in the form of a disymmetric trans double bond. To understand why such a bond can result in two configurations, one must appreciate that (concurrent) rotation about the two C-C single bonds adjacent to the alkene is in fact restricted, because to the  hydrogen labelled H<sub>a</sub> cannot easily pass by the edge of the 4-membered ring. Construct this molecule (in fact the ketone rather than the alkene)  and optimize its geometry. Note in particular that the ring junction is  ''trans'' and not ''cis''. 
# You will find you may well have obtained one of two forms.  In the first, the  H<sub>a</sub> hydrogen will be opposite the  C=O group, in the other it will be adjacent to it.  Record the energy of whatever form you got.  At the end of the course, we will try to find the ''winner'' with the lowest energy (this is not as trivial as it sounds!).  
# Next, take your structure, and try to  ''flip'' the [[trans]] alkene bond around so that eg if the methyl were previously pointing up, now it will point down.  You may find a combination of erasing/redrawing  or of  moving, will accomplish this.  You may also find another trick useful, of deleting all hydrogens, and then re-sprouting them back on again.  Re-optimise your structure and compare the energy with your first isomer. 
# Another feature of this model is that you can judge which group is in the so-called shielded region of the carbonyl group magnetic anisotropy. Using this information, you can see if there are any anomalous <sup>1</sup>H chemical shifts that might need explaining!

==== References ====
#  M. Clericuzio, G. Alagona, C. Ghio, and L. Toma, ''Ab Initio and Density Functional Evaluations of the Molecular Conformations of -Caryophyllene and 6-Hydroxycaryophyllene'', ''J. Org. Chem.'' '''2000''',  ''65'',  6910 - 6916.  {{DOI|10.1021/jo000404+}}.
#[http://en.wikipedia.org/wiki/Caryophyllene Wikipedia article]
# For a recent application of this phenomenon, see P. C. Bulman Page, B. R. Buckley, S. D.R. Christie, M. Edgar, A. M. Poulton, M. R.J. Elsegood and V. McKee, ''A new paradigm in N-heterocyclic carbenoid ligands'', ''J.  Organometallic Chem.'',  '''2005''', ''690'',  6210-6216. D {{DOI|10.1016/j.jorganchem.2005.09.015}}.

=== Germacrene:  Conformational analysis of medium sized rings ===

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#  [[Image:Germacrene.gif|thumb|right|Germacrene and the thermal reaction product]]Germacrene is a natural product with a ten-membered ring; it has the triene structure shown. Assuming that it adopts a crown conformation, build a three-dimensional model. 
# On heating, germacrene is converted into one of the stereoisomers of the divinylcyclohexane, via a [3,3] sigmatropic pericyclic reaction.  Predict  from your model for Germacrene whether the product will have the two vinyl groups [[cis]] or [[trans]] to one another.
|}

==== References ====

# K. Shimazaki, M. Mori, K. Okada, T. Chuman, H. Goto,  K. Sakakibara and M. Hirota, ''Conformational analyses of periplanone analogs by molecular mechanics calculations'', '' J. Chem. Ecology'',   '''1991''',  ''17'',  779-88.  {{DOI|10.1007/BF00994200}}.
# H. Shirahama, E. Sawa and T. Matsumoto, ''Conformational aspects of germacrene B. Are the germacrenes resolvable ?'',  ''Tetrahedron Lett.'', '''1979''', ''20'',  2245-2246.  {{DOI|10.1016/S0040-4039(01)93687-1}}. See also  {{DOI|10.1039/P19750002332}} for an explanation of the selective epoxidation of germacrene.

=== Xestoquinone: Regio and Stereoselectivity in the Diels Alder reaction===

# [[Image:xestoquinone.gif|thumb|right|Xestoquinone precursor]] This compound is a precursor to a natural product called Xestoquinone. It has four alkene groups, which can individually be considered as the alkene component in a  <sub>&pi;</sub>2<sub>s</sub> + <sub>&pi;</sub>4<sub>s</sub> [[Diels Alder]] [[cycloaddition]]. The pair of alkenes ''a+b''  or  ''c+d'' can also act as the diene component in the <sub>&pi;</sub>2<sub>s</sub> + <sub>&pi;</sub>4<sub>s</sub> [[Diels Alder]] [[cycloaddition]]. Construct a model of the product of e.g. forming a bond between alkene''a'' or alkene  ''b'' and diene  ''c+d'', and then reverse the addition by using either  ''c'' or  ''d'' adding to the diene  ''a+b''. The stereochemistry of addition should always be  [[suprafacial]], i.e. preserving the stereochemical relationships of the alkenes. You should very carefully check that this is so in your final model.
# Whilst you should stop at '''two''' models, it is  possible to construct many more.  For example, one might be able to add to either the  ''top'' face of alkene  ''b'' or to its ''bottom''face. Identify the model with the lower energy, and save it for the end of the workshop. We will identify the isomer of lowest energy from everyone's results, this being a communal  [[Monte Carlo]] experiment to find the  [[global minimum]].

==== References ====

#[http://en.wikipedia.org/wiki/Diels-Alder_reaction Wikipedia article]
#For the original literature on this synthesis, see R. Carlini, K. Higgs, C. Older, S. Randhawa, and R. Rodrigo, ''Intramolecular Diels-Alder and Cope Reactions of o-Quinonoid Monoketals and Their Adducts: Efficient Syntheses of (±)-Xestoquinone and Heterocycles Related to Viridin'', ''J. Org. Chem.'', '''1997''', ''62'', 2330 - 2331.  {{DOI|10.1021/jo970394l}}  where you can check to see which isomers actually do form!

=== Aldol Reaction and  anti-Bredt Rings ===

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# [[Image:Aldol.gif|thumb|right|Aldol Reaction]]When the diketone shown is treated with base, it undergoes an aldol condensation.  Two obvious possibililties are elimination of the combination H<sub>a</sub>  and O<sub>a</sub>,  or of the alternative combination H<sub>b</sub>  and O<sub>b</sub>. In fact, only a single product is formed.  On the basis of energies for both products, can you predict which one is actually formed? 
# Measure a few dihedral angles, ie to find out how planar the alkene present is.  Does this suggest a reason why one isomer is less stable than the other?
# There is a third very remote structural possibility. If you have time, verify that this third product truly is unlikely.
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==== References ====
#[http://en.wikipedia.org/wiki/Bredt's_Rule Bredt's Rule]
# I. Novak, ''Molecular Modeling of Anti-Bredt Compounds'', ''J. Chem. Inf. Model.'', '''2005''',  ''45'', 334 - 338.   {{DOI|10.1021/ci0497354}}
# See also this article A. Nickon, D. F. Covey, F.-C. Huang, and Y.-N. Kuo,  ''Unusually facile bridgehead enolization. Locked boat forms in anti-Bredt olefins'', ''J. Am. Chem. Soc.'',  '''1975''', ''97'',  904 - 905;  {{DOI|10.1021/ja00837a043}} in conjunction with Project 9.

=== Conformational Preference for  asymmetric hydride reduction of a ketone ===

# [[Image:Felkin.gif|thumb|right|Asymmetric hydride reduction]]The hydride ([http://en.wikipedia.org/wiki/Lithium_aluminium_hydride BH<sub>4</sub>, AlH<sub>4</sub>,  etc]) reduction of the ketone shown here is stereospecific, resulting in an alcohol with the stereochemistry shown (known as the [http://en.wikipedia.org/wiki/Chiral_induction Cram or the Felkin-Anh] rule). Construct a model of the ketone and establish which of at least two conformations is the lowest in energy.
# If the hydride anion is delivered from the least hindered position, is the conformation you have consistent with the stereochemistry shown for the product?
# You can see from Ref 4 that the situation can be far more complex, depending on many other factors.


====References ====
# [http://en.wikipedia.org/wiki/Chiral_induction Wikipedia article]
# D. J. Cram and D. R. Wilson, ''Studies in Stereochemistry. XXXII. Models for 1,2-Asymmetric Induction'', ''J. Am. Chem. Soc.'', '''1963''', ''85'', 1245 - 1249.  {{DOI|10.1021/ja00892a008}}.
# Y. Yamamoto, K. Matsuoka, and H. Nemoto, ''Anti-Cram selective reduction of acyclic ketones via electron transfer initiated processes'', ''J. Am. Chem. Soc.'', '''1988''', ''110'', 4475 -4476;  {{DOI|10.1021/ja00221a093}}.
# A. Mengel and O. Reiser, ''Around and beyond Cram's Rule'', ''Chem. Rev.'', '''1999''', ''99'', 1191 - 1224.   {{DOI|10.1021/cr980379w}}.

=== Enantiomers vs Diastereomers Part 4: NMR Coupling  constants ===

#[[Image:karplus.gif|thumb|Axial-equatorial interconversion|right]]In  Project  2.2 above, we saw how the energies of diastereomeric compounds could be compared with the corresponding enantiomers. In this extension, we show how molecular modelling can cast light on the conformation adopted by 2-ethyl-4-methyl-1-oxa-cyclopentane-3-carboxylic acid estimated using  measured<sup>1</sup>H NMR coupling constants. The (2S,3S,4S) diastereomer has couplings of <sup>3</sup>J<sub>H2,H3</sub> 8.3 Hz and <sup>3</sup>J<sub>H3,H4</sub> 9.8 Hz.  Two possible conformations of this diastereomer are shown on the right.  They differ in that one has Et axial, and  Me/COOH equatorial, and the other  Et equatorial and  Me/COOH axial.
#[[Image:karplus.jpg|Karplus plot. Click to expand|thumb|left]]By calculating the geometries of both conformations, and measuring the dihedral angle H2-C-C-H3  and  H3-C-C-H4, one can assess by using the  Karplus equation (left, taken from  Ref 2 and relevant for a cyclopentane, but the values for which might be modified by the presence of electronegative substituents), which conformation leads to the best agreement between the calculated  angle and the measured coupling constants  (Hint: on the basis of the predicted couplings, you should be able to eliminate one of the two conformations shown for this molecule).
#[[Image:5-circulene.gif|thumb|5-circulene|right]]In Project 2.2 we also introduced molecules such as helicenes and circulenes. The <sup>1</sup>H NMR of the [5]-circulene shown to the right revealed a complex spectrum at  &delta; 2.98 ppm and again at 3.75 ppm. On the face of it, the four protons labeled H<sub>a</sub>  and H<sub>b</sub>  should all be equivalent, and the spectrum should be a single peak, not two complex multiplets.  Indeed, if the  NMR is recorded at high temperatures, this is exactly what is observed.  By constructing a model of the  [5]-circulene shown, can you explain why at normal temperatures, the  NMR spectrum is so complex?<br clear="left"/>
#[[Image:Lab_expt.jpg|thumb|Synthesis lab experiment|right]]A practical application of this technique is to determine the stereochemistry of the product of the reaction between E,E-2,4-hexadien-1-ol and maleic anhydride. You will have the  <sup>1</sup>H NMR spectrum of your sample recorded, and evident from that will be peak multiplicities of the various proton resonances. You should endeavour from your analysis to come up with a suggestion for the structure of compound  '''Y''', and from this, estimates of the numerical values (but not the signs) of the <sup>2</sup>J  and <sup>3</sup>J couplings visible. Now using the techniques described above, construct a model of your proposed structure for  '''Y'''. Measure the  dihedral angles for all the  <sup>3</sup>J couplings, and very approximately estimate what the corresponding   <sup>3</sup>J  might be from the diagram above. Does this help you assign the stereochemistry of the product?
#'''Advanced topic''': Part of the spectroscopic analysis of the compound  '''Y''' involves interpreting the  IR spectrum. Theory can be used in fact to simulate the full  IR spectrum.  In section  5.3 below, you will find instructions on how to use the model you have calculated here to initiate a so called '''density functional''' calculation.   This will provide you with the required IR simulation.  Follow these instructions, and open the resulting  .log file in  Gaussview. Go to the '''Results''' menu and select '''vibrations'''.  The IR spectrum will be displayed. Does it match the one you have recorded for yourself?

==== References ====

#M. Karplus, ''Vicinal Proton Coupling in Nuclear Magnetic Resonance'', '' J. Am. Chem. Soc.'', '''1963''', ''85'', 2870 - 2871; {{DOI|10.1021/ja00901a059}}
#A. Wu, D. Cremer, A. A. Auer, and J. Gauss, ''Extension of the Karplus Relationship for NMR Spin-Spin Coupling Constants to Nonplanar Ring Systems: Pseudorotation of Cyclopentane'', ''J. Phys. Chem. A,'', '''2002''', ''106'', 657 -667;  {{DOI|10.1021/jp013160l}}
#C. A. Stortz and M. S. Maier, ''Configurational assignments of diastereomeric &gamma;-lactones using vicinal H–H NMR coupling constants and molecular modelling'', ''J. Chem. Soc., Perkin Trans. 2'', '''2000''', 1832 - 1836. {{DOI|10.1039/b003862h}}
# A. H. Abdourazak, A. Sygula, and P. W. Rabideau ''Locking the bowl-shaped geometry of corannulene: cyclopentacorannulene'', ''J. Am. Chem. Soc.'', '''1993''', ''115'', 3010 - 3011.{{DOI|10.1021/ja00060a073}}

===  Bridgehead enols: Thermodynamic vs Kinetic Control Part 2.===
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#[[Image:Bredt.gif|thumb|right|Brendanone]] The ketone Brendan-2-one shown right exhibits unusual behaviour.<sup>6</sup> When treated with NaOD/MeOD, deuterium substitution occurs easily and rapidly only in  position H<sub>b</sub>. Enolisation must of necessity form a bridgehead double bond (''anti-Bredt''),  but clearly one isomer is more stable than the other possible form.  Does molecular modelling predict this correctly?  
#The unusually facile enolisation of this ketone (given that it forms an anti-Bredt enol) can also be investigated by molecular modelling. '''Measure''' the dihedral angle between the C-Ha or C-Hb vector and the carbonyl group. Assuming that the  ''ideal'' angle for proton removal is around  90&deg;, which proton is better set up for abstraction? Might this be  kinetic rather than thermodynamic control? 
#[[Image:Cortisone.gif|thumb|right|Cortisone]]One could also revisit Problem  2.3.3 above. Here, proton abstraction forms an enol which eventually epimerises the bridgehead position to form a''trans'' ring junction. Why should this proton be particularly easy to remove? From what you have learnt above, would this be for kinetic or for thermodynamic reasons (or both?). Are all the relevant effects modelled using the mechanics approach or is consideration of the electrons  also necessary?
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==== References and Footnotes====

# A. Nickon, D. F. Covey, F.-C. Huang, and Y.-N. Kuo,  {{doi-inline|10.1021/ja00837a043|''Unusually facile bridgehead enolization. Locked boat forms in anti-Bredt olefins''}}, ''J. Am. Chem. Soc.'',  '''1975''', ''97'',  904 - 905;  {{DOI|10.1021/ja00837a043}}.

===Sulfonylation of  Naphthalene: Thermodynamic  vs Kinetic Control Part 3.===

[[Image:Sulfonylation.gif|right|thumb|Sulfonylation of naphthalene]]The sulfonylation of naphthalene using sulfuric acid is a good example of a mechanism combining both steric and electronic influences. The Molecular mechanics method intrinsic to the  Ghemical program can only model the former, and not the latter. It is a worthwhile exercise to establish whether this anticipated deficiency does indeed lead to a model which only partially explains experiment.

It has been known for some time that treating  naphthalene with sulfuric acids at low temperatures produces mostly substitution at the 1-position of the naphthalene.  Heating the reaction mixture, or conducting the reaction at elevated temperatures produces mostly the  2-isomer.  This is indeed a classic example of  [[kinetic]] vs  [[thermodynamic]] control, the 1-isomer being the kinetic one and the  2-isomer the thermodynamic one.  To model the kinetic reaction, we have to inspect the [[transition state]] for the reaction,  and here we can approximate this by the  [[Wheland Intermediate]].  To model the thermodynamic reaction, we have to inspect the product (rather than the transition state) for the reaction.

#Build models for all four species shown in the diagram on the right. For the two products, define ''conjugated'' bond types for all the ring bonds, and define the sulfonyl group with two  S=O double bonds and one  S-O single bond.  Take care to optimise the conformation of the sulfonyl group with respect to the aromatic ring. For the two Wheland intermediates, the limitations of  Ghemical will force us to ''cheat''. Ghemical does not have parameters for a carbocation.  So define the  C2-C3 bond as conjugated (for the  1-Wheland intermediate).  When you '''add hydrogens''' it will in fact add a second hydrogen to C2.  Delete this one hydrogen.  Ghemical will calculated the energy regardless of not knowing C2 is actually a carbonium ion!  For the 2-Wheland intermediate, ensure that you use '''exactly''' the same number of  ''conjugated'' bond types as you did for the  1-isomer (the two models in a mechanics sense are only comparable if you have the same total number of bond types in each model).   You will have to decide whether these (undoubted) approximations have  produced reasonable models or not (is the naphthalene framework planar for example, as it should be?).
#Record the pairs of energies (two for the  1- and 2-products, and two for each preceeding transition (Wheland) state.
#By turning the spacefilling representation on, which of the two products has the least unfavourable steric interactions between the sulfonic acid group and any adjacent hydrogens? Does this match with their relative energies?
#Do any unfavourable steric interactions observed in the product(s) also exist in the  Wheland intermediates (as models for the transition states)?
#The relative stability of the  Wheland intermediates is always assumed to be an '''electronic''' phenomenon. The conventional explanation is that the  1-Wheland isomer is stablized by both one aromatic ring '''and''' an allyl cation conjugated to it.  The 2-Wheland isomer is stabilised by one aromatic ring conjugated to a secondary carbocation and an alkene. This type of ''cross conjugation'' is conventionally assumed to be less favourable.  Does a purely mechanical approach to this problem reproduce this expectation?  Or is this ''mechanical'' approximation to an''electronic'' model too severe? It seems a good point to stop this course, since the next time you will build models, it will indeed be using methods which properly approximate the electronic components.
====References====

#R. Lantz,   ''Mechanism of the monosulfonation of naphthalene'',    ''Compt. Rend''.  '''1935''',  ''201'',  149-52.
#G. W. Wheland, ''A Quantum Mechanical Investigation of the Orientation of Substituents in Aromatic Molecules'', ''J. Am. Chem. Soc.'' '''1942''', ''64'', 900 - 908; {{DOI|10.1021/ja01256a047}}
#C. A. Reed, N. L. P. Fackler, K-C. Kim, D. Stasko, D. R. Evans, P. D. W. Boyd, and C. E. F. Rickard, ''Isolation of Protonated Arenes (Wheland Intermediates) with BArF and Carborane Anions. A Novel Crystalline Superacid'', ''J. Am. Chem. Soc.'' '''1999''', ''121'',  6314 - 6315 {{DOI|10.1021/ja981861z}}