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Conformational analysis

Six second year lectures by

Henry Rzepa (rzepa@imperial.ac.uk, Room 169, C2)

Department of Chemistry, Imperial College London.

DOI: http://doi.org/10042/a3uy9

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Blog-stories‡

Twinned course: Pericyclic reactions

Texts:

1. D. H. R Barton "Principles of Conformational Analysis", 1970. DOI: 10.1126/science.169.3945.539 and the original article (DOI: 10.1039/QR9561000044).

2. There are numerous articles on the topic in the J. Chem. Education.

3. The lectures are based on the material here rather than the texts above. These pages also contain many molecule/transition state models (benchmark 1) and surfaces (benchmark 2), which can be viewed on Desktop-type Web browsers (Firefox-27, Safari-7 or Chrome-34; Internet Explorer is compatible only for Windows 8.X) or Tablets (see tablet project).

4. Sections marked contain expanded stories in the form of a blog, and may be consulted for background reading. This material is not examinable.

5. Link to instructions for Conquest search.

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Some (local) Historical Background.

One starting point for the story is with 28 year-old Hermann Sachse. Following the recognition of the tetrahedral nature of saturated carbon in 1874 (or perhaps 1869), Sachse in 1890 using only trigonometry, derived the non-planar chair and boat conformations of cyclohexane and the axial and equatorial positions of the hydrogens. He even encouraged readers of his articles to construct a paper model to help them visualise this! Conformational analysis was well and truly born (except that no-one recognised the significance of Sachse's work, and he died in obscurity in 1893!). His work was eventually vindicated in 1918 when Ernst Mohr analysed the structure of diamond, and showed that the carbon framework adopted Sachse's chair conformation.

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In 1950 (following a 1934 theoretical analysis by William Penney, a future Rector of Imperial College), Derek Barton made conformational (and 3D) analysis a mainstay of organic chemistry, applying it to great effect to understanding the chemistry of steroids, and eventually sharing the Nobel prize in 1969 for this idea. This is commemorated in one of the graphical images adorning the student services centre in the chemistry building at Imperial. During the years ~1965-1975 he delivered the predecessor to this very course in person at Imperial College. Since then, the theoretical understanding of conformational analysis has continued to develop. Nowadays, the subject overlaps considerably with the theory and practice of molecular modelling and of stereoelectronics.

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Two of the most famous Nobel-prize winning examples of science in the 20th century use Barton's principles of conformational analysis:

1. The model of DNA built by Watson and Crick.

2. ,Linus Pauling's equally famous description of the structure of proteins.

Nowadays, much of what is now known as molecular biology is founded on these two pillars. In this course, our 3D models are obtained from either the CCDC crystal database or by calculation.

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Definitions

Scope: Most of this analysis will be applied to a series of simple organic (although the analysis can also be applied to inorganic) compounds ranging from straight-chain hydrocarbons, functionalised straight chain molecules such as alkenes, aldehydes and ketones, esters and amides, through small and medium ring cycloalkanes and related saturated oxygen heterocycles, and ending with some examples of atropisomerism.

The terms conformation and conformational analysis will be defined and illustrated. Conformation should be distinguished from the configuration.

- configuration is normally taken to mean a fixed geometrical arrangement around an atom or several atoms and which is prevented from exchanging with other configurations at "chemical temperatures" by the presence of high kinetic barriers, normally resulting from the need to actually break bonds to do so. This normally means that geometrical and optical confgurational isomers can be separated at room temperatures.

- In contrast, any one conformation is more likely to easily exchange with other conformations as part of an equilbrium process, due to much smaller kinetic barriers which are normally the result of not needing to break any bonds. These changes normally occur at one or more single bonds which are presumed to rotate about their axes with relatively low kinetic barriers. This means that, except for a few special cases called atropisomers, we cannot separate and isolate individual conformational isomers at room temperature (although it might be possible at low temperatures). A conformer of a molecule is thus regarded as synonymous with a rotamer about one or more bonds.

If we take a molecule containing a single bond bearing groups, X and Y, attached to the atoms A and B at either end of that bond then we can consider a number of isomers caused simply by rotation about that bond:

Of course, we need not choose a 90° rotation as in the above example but, rather, any degree, or fraction of a degree, between 0 and 360°. If the energy of the system is plotted as function of this rotation, one or more minima will emerge as a result. These minima can sustain molecular vibrations (i.e. they have a finite lifetime) and hence also an associated zero-point energy, entropy and free energy. We give each pose with these properties the name conformational isomers (or conformers) or just conformations.

Conformational analysis: Conformational analysis can therefore be regarded as the analysis of the poses (shapes) that molecules can adopt as a result of single bond rotations. A molecule can adopt an equilibrium between several such poses, the relative abundance of which is determined by the Boltzmann distribution, and which in turn is merely determined by the relative free energy of each pose. Conformational analysis is the study of how some properties (particularly the free energy and reactivity) of a molecule are related to its shape. The shape of a molecule is not static but is a dynamic equilibrium between a number of conformations, the preferred ones being those we would encounter more times than any other if we were to take a series of snapshots of the population, because they have lower free energies. Conformational analysis can be considered to consist of two parts.

1. Analysis of why the preferred conformations adopt the shapes that they do. This is the the thermodynamic part of the subject and it concentrates on the free energies:

- ΔG = -RT Ln Keq; R the gas constant = 1.98 cal/mol per K, T = temp and Keq is the equilibrium constant between any two conformations differing in free energy by ΔG

2. The second part concentrates on reactivity, and may be considered the kinetic part of the subject since it depends on the free energy of activation.

- Ln(k/T) = 23.76 - ΔG/RT gives the rate (of a unimolecular) reaction, where ΔG‡ is the free energy barrier and k is the rate constant (in S-1).

The theory of conformational analysis: Two concepts from quantum mechanics will be borrowed to build a framework for understanding the factors influencing the free energies of conformations.

1. The Stereoelectronic theory of structure describes how interactions between electrons in covalent bonds and lone pairs controls the relative energies of conformations.

2. The second describes how atoms in molecules interact at non-bonded distances rather longer than that of the covalent bond, being a more quantitative model for what is often called steric effects.

A Note on energies. Throughout these notes, you will find energies expressed in kcal/mol rather than kJ/mol (1 kcal= 4.1868 kJ). This is because the computer programs used all show kcal, as does much of the literature you might read on the topic.

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The theory of conformational analysis

The theory is introduced with reference to trying to explain why the eclipsed form of ethane is ~2.6 kcal/mol higher in energy than the staggered conformation (this barrier was inferred from trying to reproduce the correct entropy for ethane: DOI: 10.1021/ja01281a014). There are three effects which are added together:

- Effect one: Orbital overlap or bond orientation. Pitzer and Lipscomb first proposed in 1963 (DOI: 10.1063/1.1734572) that there was an attractive force favouring the anti-peri-planar (abreviated app) conformation due to a favourable alignment of the orbitals describing the C-H bonds. In 1979 Brunck and Weinhold (DOI: 10.1021/ja00501a009) derived equations for obtaining the appropriate orbital (which we now call Natural bond orbitals, or NBOs). These come in the form of a C-H bonding σ-orbital describing the pair of electrons located along the C-H covalent bond, and a C-H σ*-orbital describing the anti-bonding form of this orbital and containing no electrons.

A form of theory known as perturbation theory shows how the pair of electrons in such a σ-orbital interacts with the vacant σ*-orbital orbital. The result is stabilization of the filled bonding NBO (by an energy E(2)) and destabilization (by an energy >E(2)) of the antibonding NBO. Since the latter has no electrons, the overall effect is of stabilization, but only if

- if the σ-σ* energy gap is sufficiently small

- the two orbitals can overlap efficiently. This overlap is optimal for the anti-periplanar orientation.

This effect can be represented using "arrow pushing" as conjugation of the following type (X=Y=H for ethane):

In staggered ethane, there are six (equivalent) anti-periplanar interactions between pairs of a σC-H -orbital and a σ*C-H -orbital (X=Y=H), for each of which E(2) = 3.2 kcal/mol.

These anti-periplanar orientations are all missing in the eclipsed orientation, being replaced by syn-periplanar interactions for which E(2) has the smaller value of 1.3 kcal/mol each due to reduced overlap.

- Effect two: Bond-bond or Pauli repulsions. In a similar manner, one can show that the interaction between two occupied C-H σ-orbitals results in overall destabilization (the top orbital being destabilized by more than the bottom is stabilized).

- Thus the total pairwise (steric) repulsions in eclipsed ethane comprise three pairs of eclipsed C-H bonds and six pairs of C-H bonds oriented at 120°; +22.3 kcal/mol (for details, see here).

- In staggered ethane, three anti-periplanar and six C-H pairs oriented at 60° totalling +21.9 kcal/mol

Overall, these favour the staggered form (by 0.4 kcal/mol). Whilst the effect is relatively small in ethane, as molecules get larger, it mounts up! In general however, effect one is more stabilizing than effect two is destabilizing.

- Effect three: van der Waals (dispersion) forces. Whereas effects 1 and 2 operate at relatively short (bonded) internuclear distances a rather different one operates at longer (non-bonded) inter-atomic distances:

At short distances the function is strongly repulsive (see also 2 above), but at longer distances it actually becomes attractive (which is why longer chain alkanes tend to be liquids and not gases, vis petrol!). The maximum attraction occurs at a distance corresponding to the sum of the so-called van der Waals radii for the two atoms concerned. For argon, this radius is 2*1.88Å =3.76Å (above, 100 cm-1 ~0.3 kcal/mol or ~1.3 kJ/mol). For hydrogen, that radius is 1.2Å (when interacting with other hydrogens) or 1.1Å (when interacting with other elements, see DOI: 10.1021/jp8111556). In typical organic compounds, this means that maximum attraction occurs at the following distances for typical pairs of non-bonded atoms:

1. H...H; 2.4Å (becoming repulsive at ~<2.1Å unless it's a dihydrogen bond).

2. C...H; 2.7Å

3. N...H; 2.58Å

4. O...H; 2.62Å

5. Cl...H; 2.85Å

6. F...F; 2.9Å

7. C...C; 3.2Å

8. Cl...Cl; 3.5Å

9. Br...Br; 3.9Å

10. "Me"..."Me"; 4.0Å

11. I...I; 4.3Å

Od Hassel (in 1943) and Derek Barton (in 1948, DOI: 10.1039/JR9480000340) followed Bill Penney (1934) in recognising "The significance of van der Waals atomic radii for the stereochemical structure of molecules". Hassel and Barton won the Nobel prize in 1969. Remember also that whilst the interaction energy for any two atoms is relatively small (~1 kJ = 0.3 kcal/mol), the total number of such interactions goes up very rapidly for larger molecules (and it can be very large indeed for molecules the size of e.g. proteins). For ethane, the difference in van der Waals/dispersion attractions for the two orientations of ethane is tiny (~0.05 kcal/mol) but again the effect grows strongly with the size of the molecule.

For wonderfully detailed, but still readable explanations of what goes on at the surface of a gecko's foot, see 10.1002/adfm.201100493. or on the topic of bio-inspired adhesives: 10.1002/adfm.201100982. The other famous example of how attractive dispersion forces can be is the difficulty in pulling apart two telephone directories.

There is a crucial difference between the three effects. Effects 1 and 2 are highly directional (anisotropic) whereas effect 3 is isotropic, which means it depends only on the distance between two non-bonded atoms and not on their relative orientation.

Summary of important concepts

1. Conformational processes are dynamic and the thermodynamic equilibrium population of conformers about the C-C bonds is determined by:

- maximising σC-H/σ*C-H and/or σC-C/σ*C-C conjugation

- minimising σC-H/σC-H and/or σC-C/σC-C bond electron repulsion (Pauli repulsion)

- optimising van der Waals (dispersion) interactions between non-bonded atom pairs

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Conformations of Saturated, Straight-Chain Hydrocarbons: σ-σ Conjugation

n-Butane

Let us consider first in more detail molecule with which you should be familiar in conformational terms, namely, butane. The chart below summarises a number of terms in common usage in conformational studies, many of which you should have seen in the first year:

If the molecule is rotated in small increments (5°) about the central bond, the energy (for those who care, using a DFT method known as ωB97XD/6-311G(d,p)) shows up as follows.

There are two limiting conformations of butane which have a minimum of energy on a plot of energy versus dihedral angle:

1. staggered/anti-periplanar conformation

2. Gauche conformation, showing close H...H approaches

and two maxima in that plot which we call transition states connecting the conformations

eclipsed/syn-periplanar transition state

eclipsed/anti-clinal transition state

The higher energy of the eclipsed forms compared to the app or anti-periplanar form (3-5 kcal/mol) is defined as the strain and since it derives from twisting (or torsion) about single bonds this strain is called torsional strain. We shall see later that certain molecules cannot avoid a high degree of torsional strain, but for most straight chain molecules this strain can be relieved by rotation about the bond to give one of the staggered conformations.

Overall, the staggered/anti-periplanar conformation is ~0.7 kcal/mol more stable in free energy ΔG_298 than the gauche form [ΔG = -RT Ln (69%/31%)]. Can we at least qualitatively explain this in terms of the three theoretical effects listed in the previous theoretical section?

1. Effect one:

- In anti-periplanar or app n-butane (X=Y=Me), comprises four sets of σC-H/σ*C-H-orbital interactions (E(2)=3.52 kcal/mol) and two σC-C/σ*C-C-orbital sets (E(2)=2.62) = 19.32 kcal/mol.

- For the gauche conformation, we have two sets of σC-H/σ*C-H interactions (E(2)=3.49), t wo sets of σC-C/σ*C-H (E(2)=1.78) and two sets of σC-H/σ*C-C (E(2)=4.25) = 19.04 kcal/mol, which indicates app is favoured over gauche by this effect.

2. Effect two, the bond-bond Pauli repulsion energy also disfavours Gauche by ~0.37 kcal/mol.

3. Effect three, the gauche conformation has 2 H...H contacts (~2.4-2.6Å) not present in the app form, which means the van der Waals (dispersion) energy slightly favours this conformation by ~0.27 kcal/mol.

Effects two and three ~cancel, which means the anti-periplanar conformation wins out through effect one (Note: ΔΔG_298 is only very ~ ≡ ΔE(2)).

The rate of interconversion of the conformers is given by Ln(k/T) = 23.76 - ΔG/RT. For the app/gauche barrier at 298K (~ 3 kcal/mol), k = ~10^10 s-1, which is FAST. Even at 100K, it is ~10^5 s-1. which is a half-life of ~ 0.000006 seconds. These very short half-lives are what characterise conformations (as opposed to configurations which have very long half-lives).

Heptane

Given the relatively high proportion (31%) of the gauche) conformation in butane, we may expect similar conformations to contribute substantially in higher straight-chain molecules. Bartell and Kohl in 1963 (DOI: 10.1063/1.1734149) showed by electron diffraction of heptane in the gas phase that frequent gauche twists develop in the chain and they were able to estimate the relative proportions of the various conformations as shown in the following table.

This incursion of gauche forms is due to the longer distances favouring folding of the chain back upon itself, and hence setting up van der Waals attractions. There are two particularly attractive H...H non-convalent interactions (NCI) resulting from the AGAG conformation, the dispersion energy of which is now 0.7 kcal/mol lower than for the AAAA conformation.

Higher Alkanes

Medium length alkanes have significant populations with one or more gauche conformations (DOI: 10.1021/jp064811m), and by ~C17, the hairpin gauche conformation has become the lowest energy and dominant form.

~C30 exhibits a double hairpin, and ~C34 a broken paperclip form. By C58, the hairpin shape is now as much as ~12 kcal/mol lower than the all-trans linear shape.

Summary of important concepts

1. Conformational processes are dynamic and the thermodynamic equilibrium population of conformers about the C-C bonds in straight-chain alkanes is determined by:

- maximising σC-H/σ*C-H and/or σC-C/σ*C-C conjugation

- minimising σC-H/σC-H and/or σC-C/σC-C bond electron repulsion (Pauli repulsion)

- optimising van der Waals (dispersion) interactions between non-bonded atom pairs

2. In straight-chain alkanes the gauche conformation is promoted by increased dispersion interactions

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Substituted alkanes

In compounds of the generic structure, X-C-C-Y, where X and Y are both electronegative groups, the balance of conformational preference shifts from app to gauche

This is now due to the orbital overlap (effect 1 in theory) starting to dominate over the other two controlling factors. The relative energies of the σ-orbitals and σ*-orbitals of C-X or C-Y bonds have the following order:

⇐ small σ-σ* gap | large σ-σ* gap ⇒

⇐ Large E(2) | Small E(2) ⇒

low energy acceptor:

σ*C-F < σ*C-Cl < σ*C-O ≈ σ*C-+NMe_3 < σ*C-C≡N < σ*C-N < σ*C-C < σ*C-H < σ*C-Si

high energy acceptor:

high energy donor:

σC-Sn > σC-Si > σC-H > σC-C > σC-N > σC-O > σC-Cl > σC-F

low energy donor

Thus vertical E(2) values on the left hand side of this list, for which the σ-σ* energy gap is small, are large whilst those on the rhs are much weaker:

Examples: 1,2-Difluoroethane

gauche

anti-periplanar (app)

1. two σC-H/σ*C-F interactions, E(2) = 4.9

2. two σC-H/σ*C-H, E(2) = 2.6

3. two σC-F/σ*C-H E(2)= 0.8

4. =16.6 kcal/mol in total

1. four σC-H/σ*C-H, E(2) = 2.5

2. two σC-F/σ*C-F, E(2) = 1.8

3. = 13.6 kcal/mol in total

The app is thus stabilized by ~3.0 kcal/mol less than the gauche.

Examples: 1-trimethylsilyl-2-chloroethane

An example involving C-Si as a better electron donor than C-H is shown below. This time the effect is to favour the anti-periplanar conformation, since the Si-C bond is a good donor, and C-Cl* is a good acceptor empty orbital (but not the other way around, σC-Cl/σ*C-Si, E(2) = 2.3 kcal/mol)

app conformation

gauche conformation

σC-Si/σ*C-Cl, E(2) = 9.2

σC-H/σ*C-H, E(2) = 3.8

σC-H/σ*C-Cl, E(2) = 8.8 kcal/mol,

σC-Si/σ*C-H, E(2) = 3.3 kcal/mol

As one moves down the periodic table, e.g. Sn-C is a better donor than Si-C. Conversely, Br-C is a much worse acceptor than F-C, and S-C is a worse acceptor than O-C. This effect also manifests in a search of the Cambridge crystal database for many combinations.

Example: Ethanane-diol

In the case of 1,2-ethane-diol an intramolecular H-bond may also (weakly) stabilize the gauche form. A strong hydrogen bond does not form, because the O-H...O angle cannot adopt the preferred value of ~180°. Hydrogen bonds can also be thought of as arising from an interaction between a donor (Lp) and an acceptor H-X σ* interaction, and the overlap of that interaction is optimal for a co-linear angle. In that sense, the gauche effect and linear hydrogen bonds arise from exactly the same type of orbital interaction.

Example: An extreme case of the gauche effect. F-S-S-F

The record holder for the gauche effect is the molecule below:

The rotational barrier for this molecule is > 25 kcal/mol, which gives it a reasonable kinetic life at room temperatures. It thus crosses the boundary between a conformational isomer and a configurational isomer. Yes, it is also chiral (perhaps the smallest molecule capable of being so) and potentially resolvable into enantiomers.

Summary of important concepts

1. In alkanes bearing strongly electronegative groups the gauche conformation is promoted because σC-H/σ*C-X interactions become dominant, and these occur as result of

- good orbital overlap in anti-periplanar orientations

- a low σC-H/σ*C-X energy gap

2. Hydrogen bonds are related to the gauche effect in terms of their orbital orientations and interactions.

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Acyclic systems with unsaturated substituents: σ-π Conjugation

Propene (Y=Me, X=CH_2)

Propene is the simplest alkene containing such a bond. Rotation about the Csp^2-Me bond is easier than the corresponding bond in propane for two reasons; there is one group fewer on the sp^2 carbon and one of the bond angles is wider. This increases the distance between H and CH_2 if they become eclipsed, and avoids the dreaded H...H contacts of < 2.1Å (Nos 2 and 3 in the previous lecture).

Orbital alignment also plays a part (previous lecture). Thus a π-bond has a small energy gap to the low energy π*-bond (i.e. a good acceptor, which is why carrots are orange). The reciprocal arrangement of πC=C/σ*C-H also happens to be favourable, since not only is the π*-bond low in energy, the π-bond itself is high in energy (the band gap is small, making the π bond also a good electron donor, and again why carrots are orange).

πC=C/σ*C-H E2 = 3.6 kcal/mol

σC-H/π*C=C E2 = 5.4 kcal/mol

Although the ideal orbital alignment might seem to be 90° to the π-system, is only possible for one C-H at any time, and in fact the system prefers to have two C-H bonds aligned at 120° (instead of just one at 90°), which allows both the "outward leaning" C-H bonds to effectively overlap with the π*C=C orbital (its antibonding nature makes it lean outwards as well). The result of these stabilising interactions is to force an eclipsing of one of the methyl hydrogens with the cis-hydrogen on the CH_2 group:

In fact, the H...H distance of this pair of hydrogens is ~2.47Å, slightly van der Waals attractive. This is called the A1,3 eclipsed conformation. We have what is called a win-win-win situation!

There is one special case of this which in fact you are already very familiar with; the (e.g. isopropyl, R=Me) carbocation.

In this system, the low energy π*C=C NBO orbital is replaced by simply an empty p*π atomic orbital on one carbon. The +ve charge makes this orbital much lower in energy, and hence a far better electron acceptor than the π*C=C. Accordingly, the energy gap to the C-H σ-donor orbital is much smaller, making for a better interaction. The σC-H/p*π value for E2 is large: 41.6 kcal/mol. The H-H A1,3 eclipsed distance is 2.53Å.

These effects are in fact the electronic origin of the famous order of stability of carbocations that you will have seen in many other lecture courses.

cis-Butenes

This famously controversial system adopts a A1,4 eclipsed orientation (DOI: 10.3891/acta.chem.scand.24-0043) with a H...H distance of 2.1Å. The controversy is over whether the H...H interactions are in fact attractive or repulsive. The σC-H/π*C=C interaction remains significant (5.2 kcal/mol) and in fact is optimal in the A1,4 conformation, which allows the "outward leaning" π*C=C antibonding orbital to overlap effectively with similarly "outward leaning" C-H bonding orbitals

Aldehydes and Ketones

The σ-π* conjugation is greater for carbonyl double bonds than for alkene double bonds because the electronegativity of the oxygen atom lowers the energy of the π*C=O compared to π*C=C.

This increase in σ-π* stabilization is reflected in the relative pKa values for the α-protons of carbonyl compounds (16-20) compared to the allylic protons of alkenes (~43), since the greater interaction of the σC-H with the π*C=O (smaller σ-π* gap) will reduce the electron density in the C-H bond thereby making that proton more acidic.

A good example of this effect is illustrated below. The cyclic nature of this ketone means that the orientation of the α-CH protons adjacent to the carbonyl is fixed and rigid. Only the proton marked Hb is replaced by deuterium when reacted with methanol-d_1; Ha is untouched (DOI: 10.1021/ja00837a043). Thus σC-Hb/π*C=O is 5.4 kcal/mol, whereas σC-Ha/π*C=O is 0.5 kcal/mol. The greater σ-π* interaction corresponds to formation of H+, in other words it indicates how acidic the proton is. This acidity in turn arises because Hb is oriented ~60° to the C=O π-system, whereas Ha is only ~17° (i.e. more orthogonal and less capable of conjugation). This also manifests in the vibrational wavenumbers of the two C-H bonds. The less acidic one is (calculated) to be 3151 cm-1, whereas the more acidic one is 3102 cm-1.

The rotation barrier about the Me-Csp^2 bond tends to be lower for carbonyl compounds (~1 kcal/mol) than for alkenes (~2 kcal/mol) despite the better σC-H/π* interaction, and that might be rationalised by the absence of any H...H van der Waals attraction in the 2.4Å region for the former (lone-pair...H interactions do not appear to generate such attraction).

Finally, σ-π* conjugation also explains why aldehydes are less stable (more reactive) than ketones since there are fewer α-protons in the former than in the latter and, hence, fewer possibilities for overlap.

Alkyl Esters

These can exist in two conformations or rotamers about the single bond, s-cis and s-trans.

This introduces a new type of interaction, between an electron lone pair NBO orbital and either σ*C-O or π*C=O orbital. We have already seen how the π*C=O orbital is a good acceptor (low in energy). A lone pair (Lp) is an even better electron donor than a σ bond (it is only bound by one nucleus, not two), and hence not surprisingly this combination leads to large E(2) interactions.

1. Thus for the conformation with the oxygen σ lone pair (orange/purple) anti to the C=O bond (s-cis, red/blue, left), E(2) σOLp/σ*C-O is 6.0 kcal/mol.

2. The corresponding value for the conformation with this lone pair syn to the C=O (s-trans, right) has E(2) σOLp/σ*C-O 2.0 kcal/mol.

This difference accounts for the preponderance of the s-cis conformation.

A far larger effect is E2 πOLp/π*C=O 47.7 kcal/mol for s-cis, which of course is pure π-π conjugation of the type you would have seen in e.g. benzene. The value for the s-trans isomer is 43.6 kcal/mol, lower than s-cis because the π* anti-bonding orbital "leans outward" and overlaps better with the s-cis lone pair than the s-trans.

The partial π-double bond character of the O-C(=O) bond is reflected in a higher barrier to rotation about this bond (~12 kcal/mol), compared with the corresponding bond in methyl ethyl ketone at ~2 kcal/mol, although rotation is still fast at room temperature (we are still dealing with a conformational analysis rather than a configurational analysis!). The overall analysis can be summarised as:

The balance between these two ester conformations can also be affected by the solvent. The dipole moment of the s-cis conformer is 1.8D, whereas the s-trans conformation is 4.1D. Polar solvents will preferentially stabilize the latter, whilist the former will be favoured in non-polar solvents.

This conformational preference in esters is critical to understanding why e.g. the Sharpless asymmetric epoxidation reaction is so enantioselective.

Lactones are cyclic esters which are constrained to just the s-trans acyclic conformation, and may as a result be slightly more reactive (less stable) than an acyclic ester would be.

Amides

Amides continue the trend seen for esters. The πLp lone pair is an even better donor (higher in energy) than a Lp on an oxygen, because the nuclear charge on the N is smaller than O, and hence the lone pair is even less strongly bound by the nucleus. The σLp lone pair does not even exist for amides (it having been sequestered by one N-R).

Amides with an NH group do prefer to favour the s-cis form by ΔG 2.5 kcal/mol over the s-trans conformation

1. s-cis form: E2 πLp/π*C-O 90.5 kcal/mol, σN-H/σ*C-O 4.2

2. s-trans: E2 πLp/π*C-O 83.2 kcal/mol, σN-Me/σ*C-O 2.6

Both the π-π and σ-resonance favour the former, along with two short contacts (H...H 2.23Å, O...H 2.34Å). The second of these may be a weak hydrogen bond rather than a weakly attractive van der Waals effect (there being a continuum between these two descriptions).

Implications for Proteins

The πNLp/π*C-O E2 interaction in amides is almost twice as large as for esters, and hence the rotational barrier about the N-C(=O) bond is also much higher (~18-20 kcal/mol). This particular conformational effect it could be argued is the most important in all of biology since it determines the structure of all proteins and enzymes. Put simply, this rotational barrier has the appropriate value for life to evolve at ~37°C (a higher barrier would result in over-rigid proteins, a lower barrier would result in over-floppy proteins)

The s-cis conformation of the peptide bond also controls important aspects of the higher-order structure of poly-aminoacids (peptides), such as their propensity to form a right-handed α-helix. The conformational analysis of peptides is often represented in terms of two other important dihedral angles Phi and Psi about the backbone sp^3 carbon linking two amide groups.

Historical note: In 1951, Linus Pauling (DOI: 10.1073/pnas.37.4.205) used this information to propose a structure for how proteins fold. He built models which were based on the s-cis conformation of amides and the planarity resulting from the restricted rotation about the C=N bond of the peptide linkage, together with N-H...O=C hydrogen bonding. These assumptions enabled him to reduce the complexity of the models to a solvable extent. If you want to find out more, go read this gripping article.

Summary of important concepts

1. Simple alkyl-substituted alkenes adopt the A1,3 eclipsed conformation because of σ-C-H/π*C = C overlap/conjugation

2. Aldehydes and ketones prefer the A1,3 eclipsed conformation because of σ-C-H/π*C=O overlap, which is greater than for alkenes because of a lower energy gap

3. Esters and amides are planar because of LpO or N/π*C=O overlap/conjugations, with even smaller energy gap

4. For esters and amides, the effects due to parallel π-overlaps are far greater than those due to antiperiplanar σ-overlaps.

5. Esters and amides prefer the s-cis conformation due to antiperiplanar σ-overlaps and Hydrogen-bond style attractions

6. Rotation about N-Csp^2 is slow at room temperatures in amides due to the large degree of LpN/π*C=O conjugations, and is a major feature of the folded structures of proteins.

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Cycloalkanes

Rings, and particularly cyclohexane, is where conformational analysis started. We will deal here only with ring sizes 3-6 initially, and return to larger ones later.

Cyclopropane

The ring structure of cyclopropanes is necessarily flat. It is actually quite a common motif, and occurs in many natural produucts. This shape confers torsional strain along each of its C-C bonds because the substituents, which project above and below the plane of the ring, cannot avoid being eclipsed. Because of this eclipsed nature of the bonds, the σ resonance is rather lower σC-H/σ*C-H E2 1.5 kcal/mol than that found for ethane.

The substituted vinylcyclopropane is rather more interesting for the same reason. A σC-C/π*C=C alignment is worth E2 = 5.0 kcal/mol, and a πC=C/σ*C-C alignment 4.3 kcal/mol. This in turn sets up a conformational preference about the C-C= bond; ν 105 cm-1.

Cyclobutane

Cyclobutanes may deviate slightly from the planar conformation and thereby switch to one which is called the puckered conformation

In the puckered conformation substituents on vicinal carbons are twisted slightly out of the eclipsed arrangement thereby relieving the torsional strain somewhat. However the puckering process can only be taken so far before the distance between the two R groups enters the repulsive van der Waals region.

The energy difference between the planar and puckered conformations of many cyclobutanes is not large (<1 kcal/mol) and it is often difficult to decide simply by inspection which conformation will be adopted. Thus, the trans-1,3-dicarboxylic acid has a planar arrangement in the solid state (by X-ray analysis) and the puckered state in aqueous solution (by the lack of symmetry indicated by Raman and IR studies); in contrast its dianion is planar in solution. In contrast the cis-1,3-dicarboxylic acid is puckered in the solid state. Trans-1,3-dibromoderivative is also puckered since it shows a dipole moment of 1.10D which corresponds to a puckering angle of 143°.

Cyclopentane

Along with cyclohexane, this motif is the most common saturated ring system. To study its conformational preferences, we will adopt a new technique. This involves optimising the geometry of the ring with the constraint that all the ring carbon atoms are restricted to co-planarity. This geometry is then subjected to a vibrational analysis, and the result normal vibrational modes (3N-6 of them) are inspected to see if any of the force constants they derive from are negative. If one force constant is computed negative, then we have found a transition state, and this in fact was the case for cyclobutane above.

In the case of cyclopentane, two negative force constants are computed. This means that the planar geometry has precisely two ways of distorting to reduce the energy of the system. The eigenvectors corresponding to each of these force constants can be displayed as a twist or as a buckle resulting in more or less two isoenergetic conformations which have respectively a C_2 axis of symmetry (also called a half-chair) and a Cs plane of symmetry (also called an envelope). Neither achieves full staggering of the C-H bonds, nor do the C-C-C angles achieve the ideal 109.47° angle, so each is a compromise.

The half-chair conformation has the distinction of being almost the smallest organic compound to exhibit chirality (αD = 13.6°), although the barrier to enantiomerisation is so small that it is impossible to prevent at normal temperatures (the smallest is probably the isopropyl cation mentioned in the previous lecture).

Five membered rings have another distinction, featuring in the ribose sugar unit in DNA and RNA. The envelope conformation adopted by this ring is critical in understanding the conformation adopted by DNA itself (which features three important conformations itself, comprising a combination of that for the ribose and that of the helix itself, and which are known as A-DNA, B-DNA and Z-DNA).

Cyclohexane

This is where the conformational analysis story started, and since its an enormous topic, we can only cover a tiny fraction of what is known here. Let us start in the same manner as cyclopentane, namely calculate the force constants for planar cyclohexane. This time, three negative force constants are computed, each leading to a chair, a twist boat and boat.

Something odd happens with the boat, since it too has one negative force constant (the first two have none), and it turns out that the vectors of this force constant correspond to the transition state for enantiomerisation of the twist-boat structure (which is again chiral, (αD = 38°). Cyclohexane then has only three conformations, the chair and two (enantiomeric) twist-boats (only the latter being chiral). Historically, the first investigation of the interconversion between these chair and boat forms was as far back as 1938 (DOI: 10.1021/ja01277a020).

The experimental determination of the relative energy of the twist-boat form compared to the chair form was made in 1975 (DOI: 10.1021/ja00844a068). Cyclohexane vapour at 1000K, which contains a much higher proportion (~30%) of the twist boat form than is present at room temperature (~0.1%), was rapidly cooled and condensed onto a CsI plate held at 20K. An infra-red spectrum of this cold-trapped cyclohexane indicated extra bands due to the twist-boat form compared to a sample cold-trapped from room temperature which only shows bands due to the chair form. By looking at the rates of loss of these extra bands, the separate rates of conversion of the twist-boat form to the chair form at temperatures between 72.5K and 74K could be determined and the fairly accurate estimate of the energy, above, of the twist-boat form was made from that data, it being around 5 kcal/mol higher than the chair at room temperatures.

The crystal structure of pure cyclohexane has now been determined and it indeed confirms the chair form. It also has one other remarkable property, which often causes confusion in laboratories; a melting point of 6.5°C (it crystallises in ice, and this crystallisation can be the source of much confusion). The origin of this unexpectedly high melting point (for an alkane) might be the attractive H...H contacts (of ~2.5Å) possible in the crystal structure, which cummulatively could serve to make the lattice quite rigid (but the case is not entirely convincing).

Starting with this chair conformation, we note that the twelve hydrogen atoms in cyclohexane form a set of six which are axially oriented, and another set of six which we call equatorial. We know however that at room temperatures, cyclohexane exhibits only a single sharp 1H NMR resonance for all twelve hydrogens. Of course, this process may be slowed down at low temperatures and when sufficiently cold (~203K, see DOI: 10.1021/ja9714898) two lines appear in the 1H NMR spectrum of cyclohexane-d_11

It took a few years to work out how the two sets of hydrogens interconvert with each other:

1. Starting with one form of the chair

2. one of the CH_2 groups starts a twist motion to reach a transition state called the twisted half-chair (and in the process of twisting, becomes chiral),

3. and then drops down to reach one enantiomer of a twist boat.

4. The momentum of the previous step carries the system to a further twist leading to a boat transition state which represents the half way point of the journey. This has a mirror plane of symmetry (and so is not chiral).

5. The second half of the motion is in effect the mirror image of the first, at the end of which the two sets of hydrogen atoms have exchanged their environments. The high-energy point of this journey (the twisted half-chair transition state) represents passage over a free-energy barrier of ~10 kcal/mol.

This process can be summarised by

Since most cyclohexanes exist in the chair form rather than the much higher energy twist-boat form (for a rare example of the latter, see here) conformational analysis is almost exclusively applied to substituents on cyclohexanes in the chair conformation and this conformation will form the mainstay of our discussions.

Methyl and t-Butyl Cyclohexane

When cyclohexane is mono-substituted, the substituent can occupy either the axial or the equatorial position. In fact almost all known such substituents occupy the latter, although the reasons are due to all three factors discussed in previous lecture.

1. σC-C/σ*C-C, σC-H/σ*C-C and σC-H/σ*C-H anti-periplanar conjugations all tend to favour the equatorial over the axial conformation. Thus for methylcyclohexane, there are four app sets of these conjugations at the substituted carbon, which sum to 12.9 kcal/mol for methyl equatorial, and 12.2 for methyl axial.

2. the van der Waals (dispersion) attractions on the other hand favour axial, by 0.5 kcal/mol.

3. the bond electron (Pauli) repulsions adjudicate in final favour of the equatorial form by 1.8 kcal/mol. The experimentally measured difference for methyl cyclohexane is ~1.7 kcal/mol. This value arises mostly from filled pair repulsions involving the parallel 1,3,5-C-H/C-Me bonds, which are absent in the equatorial form and which are referred to as 1,3-diaxial compression.

4. One can also regard the axial conformation as having TWO C-X (X=Me) gauche orientations with the adjacent C-C bonds (blue), whereas these are both antiperiplanar in equatorial conformation (red), and hence the axial form is disfavoured for the same reason that e.g. gauche butane is.

For a substituent X=tButyl, the 1,3 diaxial repulsions and other geometric distorsions result in a greater energy difference; 5.9 kcal/mol, which when used in the expression ΔG = -RTLnK, indicates K >20,000 in favour of the rhs. This indicates that this large substituent effectively locks the equilibrium into a single conformation (see this crystal structure and also doi: 10.1021/jp0550311). When t-butyl and iodine are placed into competition, the t-butyl wins!.

Reactions of cyclohexanes

Earlier, we saw how anti-periplanar alignment of a donor bond orbital with an acceptor antibond orbital could explain conformational preferences in heteroalkanes. Exactly the same principle applies to a transition state of a reaction, except that the effect is actually much larger than for equilibrium geometries. The fixed anti-periplanar relationships shown below can be exploited:

1. in e.g. E2 elimination reactions: X=H (donor bond) Y=Cl (acceptor bond) shown in red

2. ring contraction (or expansion) reactions: X=OH (donor lone pair/donor bond), Y=OTs (acceptor bond) shown in blue.

3. A tutorial problem which explores this topic with a worked example is available

4. A blog on the competition between an E2 elimination and an alternative ring contraction starting from a 1,2-dichlorocyclohexane in which one chlorine is axial (and eliminates) and the other is equatorial (and induces ring contraction).

There is a vast body of chemistry dealing with both other substituents, and multiply substituted cyclohexane rings most of which is beyond the scope of the present lectures. Only two examples are noted here:

1. trans 1,2,3,4,5,6-hexa-isopropylcyclohexane can potentially ring-flip so that all six isopropyl groups are either all axial or all equatorial. You might imagine (from the above results for a single tButyl) that an all-equatorial conformation would always be far lower than the all-axial. But the crystal structure (DOI: 10.1021/ja00181a036) shows that its the latter which exists in preference to the former!

2. If the group is slightly smaller (ethyl) it now prefers a hexa-equatorial conformation.

The lesson we learn here is that when two large groups are on adjacent atoms in the cyclohexane ring, the di-equatorial conformation can result in increased steric repulsions between the two groups. Under these circumstances, the ring may flip to a di-axial conformation, where the two large groups are now as far apart as they can be (for an example see here), but where each of these groups now encounters more 1,3-diaxial compressions themselves. This can all be summarised as follows:

1. The larger of the two substituents at any ring carbon will favour the equatorial position.

2. Two large groups in a 1,3 di-axial orientation is not favoured.

3. If two large groups are on adjacent ring carbons, the balance between di-equatorial and di-axial, or the balance between axial-equatorial and equatorial-axial may be quite even, depending of course on the size of the groups.

4. As more large groups (iPr or larger) occur on adjacent ring positions, axial orientations gradually become favoured, until with hexa-substitution, an all axial orientation dominates.

5. A tutorial problem illustrating these aspects is available here.

Decalins

Another way of locking a cyclohexane ring is to fuse it with a second such ring, to form a ring system known as decalin.

In trans-fused decalin, the two rings are merged using equatorial bonds, and this now prevents either of the two chair conformations of ring A or ring B from flipping, or swapping the axial/equatorial substituents. This locked conformation can again be exploited in reactions. In the diagram below, starting from assigning the two ring junction substituents as axial, the rest of the two rings can be inferred. Thus all the substituent bonds shown in red are axial and are anti-periplanar with respect to each other. This allows e.g. elimination reactions (which require an anti-periplanar relationship) to occur using such substituents. The ring bonds themselves also inherit anti-periplanar relationships (two examples of which are shown in blue or magenta) and these can be used for migration/ring contraction/elimination reactions involving the rings themselves.

By discovering 100s of examples in the very large area of steroid chemistry (rings A and B above are the first of four rings in steroids), and classifying them according to the rules above, Barton created the area of conformational analysis, and in the process won the Nobel prize.

Homo-DNA

The conformational property of five-membered-ring pentoses in the structure of DNA was noted above. It is a curiosity that analogous six-membered-ring hexoses do not promote strong helicity in homo-DNA (DOI: 10.1021/ja062548x), it is thought because they are TOO rigid. As with the C=N character of a peptide bond, we see again that life is amazingly finely balanced! Without a way of folding DNA efficiently into a duplex (and the helix is very efficient), there would be no replication mechanism!

Summary of important Concepts

1. Cyclopropanes are flat

2. Cyclobutanes may avoid some of this strain by adopting a puckered conformation

3. Cyclopentane has two common conformations, a chiral twisted form with C_2 symmetry and an envelope with Cs symmetry.

4. Cyclohexane has three conformations, prefering a chair conformation over (two enantiomeric) higher energy twist-boat forms.

5. The axial/equatorial positions in chair cyclohexanes equilibrate through the (chiral) twist-boat conformation (ring flipping)

6. The substituent in monosubstituted cyclohexanes adopts adopts an equatorial position over the alternative axial position

7. When large groups are on adjacent carbons in a cyclohexane, the preference of di-axial/di-equatorial or axial-equatorial/equatorial-axial depends on the size of the group.

8. Conformations without 1,3-Diaxial compression are favoured.

9. Ring flipping is prevented in trans-decalin or inhibited in t-butyl cyclohexane derivatives

10. In conformationally locked cyclohexanes and decalins, anti-periplanar relationships are key to understanding their reactions such as E2 elimination, ring contraction or expansion.

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Hetero-cyclohexanes

One derivative of cyclohexane with great biological significance is oxa-cyclohexane, better known as a tetrahydropyran, one (hydroxy) derivative of which is of course D-glucose (a pyranose). As one might expect, the tetrahydropyran ring adopts a chair conformation and is largely similar to cyclohexane; thus the energy barrier for ring flipping is about 10 kcal/mol in each case.

There is, however, one major effect which is much stronger in tetrahydropyrans than in cyclohexanes, and is induced by the presence of oxygen lone pairs which replace some C-H bonds. Historically this effect was seen first in sugars and hence our discussion will start from them. D-Glucose is a hemiacetal and exists in equilibrium with its open-chain aldehydic form. Closure to the ring form from the latter leads to two diastereoisomers at the hemiacetal carbon, which are called Anomers. The one with the resultant hydroxyl group up is designated the β-anomer whereas the one with the hydroxyl group down is called the α-anomer:

In conformational terms the β-anomer may have all the groups equatorial in one chair conformation and all of them axial in the alternative ring-flipped chair conformation. However (as with a t-butyl substituent), the former prevails by a big margin (the difference in free energy is approximately 5 kcal/mol, i.e. ~ 10000 : 1) and ring flipping is again essentially suppressed. In the α-anomer all the groups are equatorial except the anomeric hydroxyl which is now axial. At equilibrium in water the β-anomer dominates, an effect which is thought to be induced by solvation and hydrogen bonding (the equatorial anomer has a ~2D dipole moment, the axial one is close to zero). For a recent exploration of the conformation of such molecules, see doi: 10.1021/ja312393m.

However, when the anomeric substituent cannot hydrogen bond (e.g. OMe rather than OH), the α anomer clearly dominates as it is also predicted to do in non-polar or non-hydrogen bonding solvents.

We have seen the origins of this exial preference previously, as resulting from σLpO/σ*C-X conjugation. Lone pairs are less tightly bound than the electrons in a C-H bond, therefore higher in energy, leading to a smaller σLpO/σ*C-X energy gap and a larger E2 (16.3 kcal/mol in this example, X=OR).

For the β-anomer, only one such interaction can be set up (red; E2 18.1 (app) and the much smaller 5.4 kcal/mol (sp)); for the α-anomer, two app interactions are now possible (red and blue; E2 16.3 and 16.3 kcal/mol, both app) including the ring oxygen, which explains the α-dominance in non-hydrogen bonded systems. In arrow pushing terms, this corresponds to the resonance/conjugation shown above. If either lone pair (on O or X) is aligned anti-periplanar (app) with the adjacent C-O/C-X bond, the conjugation will be strong. If it is not aligned, it will be weak.

In this next example, there are two app alignments (blue and red in above diagram), which need not be equal. Thus when X=Cl, the LPO/σ*C-Cl (blue arrows above, click here for actual orbitals) E2 is 25 kcal/mol. Putting electrons in the σ*C-Cl orbital lengthens the C-Cl bond (blue arrows above, blue bond below). The alternative arrow pushing LPCl/σ*C-O (red arrows above) is smaller: E2 = 10.3 kcal/mol. Overall therefore the C-Cl bond (blue bond below) in this example is lengthened more than it is contracted.

If an equatorial chlorine is added as shown above (red bond), there is no anti-periplanar LP[O]/σ*C-Cl alignment, only gauche. However, the alternative LPCl/σ*C-O alignment IS antiperiplanar, E2 11.3 kcal/mol which means the red C-Cl bond is now shortened rather than lengthened.

The result is that for this dichloropyran, the two C-Cl bond lengths in this molecule become distinctly different, one lengthened (blue) one shortened (red). Likewise, the two C-O distances also become different and these effects are confirmed by an X-ray structure. This variation in anti-periplanar alignments/conjugation in sugars is what makes their chemistry both complex and interesting.

Conformational analysis can also be applied to inorganic ring systems. For example, the very involatile cyclotriborazane B/N ring system is isoelectronic with cyclohexane, and it too adopts a chair conformation (from X-ray analysis). The red hydrogens stack above the blue hydrogens in the crystal lattice forming dihydrogen bonds and making for a very rigid and hence high melting solid.

DNA again!

The classic heterocycloalkane is the ribose ring in DNA. This system exhibits a number of (interdependent) effects we have been discussing in this course:

1. A furanose oxygen approaches to within 2.85Å of a guanine ring, some 0.3Å shorter than the combined van der Waals distances.

2. A furanose OC-H hydrogen approaches to within 2.48Å of a second furanose oxygen, ~0.14Å shorter than the combined van der Waals distances.

3. It is facilitated in this approach by being more acidic than normal due to a C-Hσ/C-Oσ* anti-periplanar interaction (E2 5.8, magenta bonds)

4. These interactions help orient the guanine to set up a strong anomeric interaction between it and the ribose; NLp/C-Oσ*; E2 11.6 (violet bond).

5. In contrast, the cytosine-furanose link avoids the classical anomeric effect, and instead sets up a weaker one with a C-C bond instead (E2 6.8, indigo bond).

6. Notice the gauche-like conformation of the ethane-1,2-diol fragment (gold bond).

Summary of important Concepts

1. Tetrahydropyrans mimic cyclohexanes in preferring the chair conformation

2. In glucose derivatives the ring flipping process is prevented by the large number of substituents (3 x OH and CH_2OH) in equatorial positions

3. Electronegative groups at the anomeric carbon prefer the axial orientation (the Anomeric Effect) because of the stabilising overlap of Lp and σ*C-X orbitals

4. Lp orbitals are better than C-H orbitals in interacting with σ* orbitals.

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Larger rings and Atropisomers

Cyclo-octane

As the rings get larger, the conformational complexity starts to increase. A cyclo-octane ring now has six conformational minima but only two of these have significant populations at room temperatures, a boat-chair and a crown (or this unusual example).

Neither of these conformations has entirely optimal bond angles or twist angles however, and so these medium sized rings are somewhat strained. There are also so-called transannular contacts between hydrogens across the ring that may be van der Waals attractive (H...H ~ 2.1-2.2Å) along with anti-periplanar relations which can mediate reactions (beyond the scope of this lecture). Many natural products have rings this size or larger. .

Larger cycloalkanes

Before we leave the cycloalkanes, here is the crystal structure of cyclo-C[24]H[48] which combines the features of the longer chain acyclic isomers (i.e. the gauche conformation leading to short H...H van der Waals attractive contacts) and the chair-like motif of the cycloalkanes, but also with something of a frustrated Gecko motif!

Cyclo-alkenes

Trans-Cyclo-octene: Chiralty and Atropisomerism

The is the smallest sized ring which can accomodate a trans-alkene into the ring system (trans-cycloheptene is very unstable, isomerising to the cis-alkene at room temperatures by rotation about the C=C bond, DOI: 10.1021/ja055388i). These systems are of interest because they introduce a new conformational phenomenon, that of atropisomerism.

Definition of atropisomerism: Atropisomers are stereoisomers resulting from hindered rotation about one or more single bonds, where the energy barrier to rotation is high enough to allow for the isolation of the conformers. This normally means that the conformers should interconvert with a half-life of ~10^3s at a given temperature; at 300K this implies a barrier of ~22 kcal/mol.

Trans-Cyclo-octene itself is disymmetric, having only a C[2] axis of symmetry, ( X-ray) and it is therefore not superimposable upon its mirror image (its optical rotation, [α]D ~464°). So we can see that atropisomerism is a special case of a conformational isomer also being a configurational isomer (the boundary between these two is ~ the half-life as defined above).

In fact, the two enantiomers can be separated by forming a diastereomeric complex with a chiral platinum salt (DOI: 10.1021/ja00903a049)

Once separated, the:

1. trans-cyclooctene enantiomers only interconvert when heated to around 184°C (ΔG‡ 35 kcal/mol, DOI: 10.1021/ja01094a021)

- Ln(k/T) = 23.76 - ΔG/RT for relating ΔG‡ to the rate of a (unimolecular) reaction at a specified temperature.

2. trans-cyclononene racemised at ~50° (ΔG ~20 kcal/mol)

3. trans-cyclodecene racemised at below room temperature (ΔG ~10 kcal/mol).

This enantiomerisation occurs by simultaneously rotating about the two single bonds shown in red (above), which involves an alkene hydrogen rotating around to point into the ring itself. The smaller the ring, the greater the transannular (repulsive) contacts there will be, and the more the rest of the ring will have to distort to reduce them.

An example of a natural product which exhibits this behaviour is caryophyllene, which contains a trans-alkene in a 9-membered ring and which can exhibit atropisomerism not only across the alkene but also the carbonyl group! This latter introduces the concept of conformational atropisomerism resulting from angular strain (seen also in the natural product Taxol).

Chirality and Conformations: Restricted rotation about a single C-C bond

Here we are concerned not with molecules that have an asymmetric carbon but rather with those which are asymmetric by virtue of their shape alone, and whose enantiomeric conformers may be interconverted simply by rotation about a single C-C single bond. In order that the enantiomers may be separated at room temperature the barrier to rotation must be reasonably high (> 20 kcal/mol, e.g. trans-cyclononene). Examples of acyclic systems which can be so induced to restrict rotation about a single bond include biphenyls and binaphthyls (the latter, when one aryl ring is naphthyl is a very valuable ligand for inducing asymmetric catalysis).

An energy profile for rotating 360° about the central (red) bond for biphenyl (X=Y=H) reveals two conformational minima which are in fact enantiomers (each has D_2 symmetry) separated by two different transition states. The profile reveals two opposing forces in action. In one transition state, maximising π-π conjugation by enforcing the two aryl rings to be co-planar also forces the two pairs of ortho hydrogens to be too close, thus raising the energy. In the other transition state where the two rings are orthogonal, the two pairs of ortho hydrogens are far apart and do not interact (either repulsively or attractively). But, the π-π conjugation across the rings is completely lost. In the two (enantiomeric) conformational minima in which the rings are oriented at 45°, the H...H distances are now in the attractive van der Waals region, and the 45° orientation allows a fair bit of π-π conjugation. This accounts for why we now have a minimum rather than a transition state (a win/win).

Transition state @0° ≡ @180°

Cause: H...H clash

Transition state @90° ≡ @270°

Cause: loss of π-conjugation

Minimum @40° ≡ @140° ≡ @220° ≡ @320°

Enantiomerisation IRC via 0°/180°

Enantiomerisation IRC via 90°

The small barrier to rotation (~ 2.5-3.0 kcal/mol) means that at room temperatures rotation about the central bond will occur rapidly, thus allowing enantiomerisation of the two minima to occur. If however, as the groups X and Y are increased in size, a quite different rotational energy profile emerges.

Rotation of 2,2'-dichlorobiphenyl‡ (X=H, Y=Cl)

High energy route: IRC via 180°

Cause: Cl...Cl clash

Low energy route: IRC via 0°/360°

Cause: H...Cl clash

‡ The artefacts are due to an imperfect reaction coordinate

Two transition states occur when the aryl rings are co-planar, with close approaches of H...Cl in one, or Cl...Cl in the (higher energy) other. The 45° minimum has vanished, and only two (again enantiomeric) 90° minima remain. Passing through the (lower energy) transition state requires ~20 kcal/mol for racemisation to occur. By making R_2=R_4 even larger (I,CO_2H, etc) thermal racemisation can be completely suppressed and these compounds can be prepared as pure enantiomers by suitable resolution. With binaphthyl, the barriers are even larger, and a wide variety of such compounds have been prepared, resolved and in many cases adapted for use in asymmetric catalysis.

The next example tries to join up some of the types of compound discussed in this course, in illustrating atropisomerism in aryl amides. The individual enantiomers of such atropisomers are can be recognised by certain enzymes!

A final (contemporary) example: Driving a Molecular car

Several of the themes discussed here are reflected in how this nano-car drives!

Helical conformations

The two preceeding examples also hint at a very important area of conformational analysis related to systems with helices (the trans-cyclo-octene can be regarded as a very simple helix). The best known example is DNA, and this is a vast area of conformational analysis we have no further time to go into!

Summary of important Concepts

1. Cyclo-octenes can exist as crown or chair-boat conformations

2. Trans-cycloalkenes have either no symmetry or a C2-proper axis of symmetry and can exist as enantiomers by virtual of restricted rotation about two C-C bonds

3. The ease of racemisation of trans-cycloalkenes increases as ring size increases

4. Biphenyls substituted with ortho substituents can exhibit restricted rotation about the central C-C bond

5. If the ortho substituents are large enough, the two conformers (rotamers) can be resolved into enantiomers

6. Such chiral biphenyls and binaphthyls can be used for asymmetric catalysis.

Don't forget to fill out SOLE!

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Help and explanations of these lecture notes.

1. These notes are what is called streamed; this means you have to be online to use them (streamed means repeated viewings require repeated downloads) There are alternative presentations, which include

1. Panopto materials (audio + non-interactive visual capture of these notes). This is also streamed using the Panopto app (on tablets)

2. Audio + non-interactive visual capture of these notes, in a non-streamed download-n-go format using the iTunesU app (on tablets). Once on the tablet, the notes can be used with no online access.

3. A non-interactive eBook presentation, again a non-streamed download-n-go format using a variety of epub-compatible tablet apps (for example on an iPad, iBooks, Kindle, Nook, Kobo etc). Some of these apps will display the animated diagrams (but some do not). The challenge of creating a fully interactive download-n-go version using e.g. the epub3 standard will be fulfilled at some stage in the future.

2. Layout. The navigation toolbar along the top allows access to the notes for any individual lecture, along with problem examples. The notes are presented in continuous galley-form, to allow facile scrolling if e.g. using a tablet. Below that is a Google search box, where only the contents of the lectures have been indexed. The third row allows control of the interactive aspects of the notes (see below).

3. Why interactive? Pericyclic processes show a wide diversity of factors which control their outcome. The symmetry characteristics of the wavefunctions, and the aromaticity that may or may not ensue, have been dealt with in the main section of this lecture course. But electronic symmetry does not always allow a single reaction path to be predicted; often two or more "allowed" pericyclic processes can be identified, and to further distinguish them, other factors such as steric effects, hydrogen bonding, etc must be taken into account. It is important to evaluate each effect quantitatively, since sometimes they might act in the same direction, sometimes in the opposite, and it is only by adding all the effects together that the final outcome can be predicted. The technique that allows this to be done is called molecular modelling, and in this particular context, since electrons are involved, it is often referred to as quantum molecular modelling. In the examples scattered throughout this lecture course, modelling was done at the DFT ωB97XD/6-311G(d,p) level, using the Gaussian 09 program. This technique is illustrated in the third year Computational modelling laboratory course. The models built using these techniques are incorporated into these lecture notes.

- Sometimes more information regarding the visual model shown here may be needed. To facilitate this, most of the models are linked to a digital repository entry for the calculation that generated them. There you can retrieve the original input for the calculation, along with a selection of output files. These can be used to re-generate the model, either exactly as previously computed or with variations of your own choosing.

4. Jmol vs JSmol.The course notes contain interactive elements rendered using the Jmol/JSmol environment, which allows these components to be viewed on a wide range of devices, including most Tablets.

1. JSmol. This is the default environment for a window that appears when show is toggled. It uses Javascript to produce 3D models of molecules and their properties. This should display in most browsers and devices.

2. Jmol. This can be toggled on if your device supports Java. Whilst most desktop computers can support Java, it may not necessarily be installed. The advantage of using this option is that the rendering of the 3D models is much faster (from 5-fold to up to 20-fold) than Javascript. Jmol is not available for the iPad.

3. Show/Hide. This produces a fixed window in the bottom right of the screen. It stays in place even if the page itself is scrolled. By default it is hidden, and if you do want to see any models, you should first show it.

4. Spin. This rotates the model about the Y-axis.

5. Vibrate. If the model is a transition state, the imaginary normal mode will be displayed as green vectors and the model will animate.

6. Anti-alias. This will sharpen up the bonds and atoms in the model, at the expense of slower rotation of that model.

7. Saving model data. From the interactive window, right-click and scroll down to the file option. Select save a copy of XXX (where XXX is the name of the file loaded, normally a calculation log file) and you will have an opportunity to save the file to your file system (desktop computers only).

5. Images. To allow most images to scale without loss of resolution on devices such as tablet computers, a scaleable vector format has been adopted here called SVG (a format written directly by ChemDoodle, and indirectly via EPS by ChemDraw). Whilst most browsers nowadays support this format, there is one exception; Microsoft's Internet Explorer browser series. If you want to see these diagrams, do not use this browser. Some animations (which are too slow to compose using e.g. Jmol) are pre-rendered into a GIF animation.

6. 2D Printing. The notes are designed to be interactive. This means displaying some elements only on demand, and including both animations and rotatable models. The notes have been optimised for these tasks. However, the print functionality of the browser is available for anyone who wishes a printed copy. The print copy will probably not faithfully reproduce the interactive elements, but the text and images should be captured. Different browsers may respond differently in the way they try to handle these components, and you have to test the browser to see if it achieves the result you desire. The safest option is to use the link provided to print, since this automatically hides the toolbar and the interactivity window before printing.

7. 3D Printing. Sometimes a tactile inspection of a 3D model can carry additional insight. 3D printing also allows one to go beyond the traditional ball&stick model to representation of more complex surfaces, such as molecular orbitals and such models can be accurately quantitative, representing e.g. transition states and other computable objects. A small library of such objects is held here and will be added to over time.

8. Tablet devices. These notes have been tested on the following types of tablet:

1. Apple iPad (IOS 7).

2. Hudl (Android 4.2)

3. Samsung (Android 4.2)

If you have a tablet not listed here please let me know, both if it works and especially if it does not (although a fix may not necessarily be possible). A pilot project for the evaluation of the use of tablets for lecture notes is documented here. All Imperial College students have read/write access to this project page, and constructive comments there are warmly welcomed.

9. Tablet annotation and note taking.. One of the advantages of these devices is that one can annotate/take notes. There are many ways of doing this, but these two are relevant to chemistry:

1. Annotation using Diigo. This allows sticky notes to be attached to any Web-page (including this one) or selections of text to be highlighted. You will have access to the notes every time you re-open the page. The notes are stored in a specified account, which can be either Diigo themselves, or Google/Facebook etc.

- On a desktop browser, you will need to install the Diigo extension into the browser (e.g. Firefox, Chrome). In the Imperial environment, this will need to be done only once (on conventional desktop computers or laptops).

- On a tablet, you can use a native Diigo browser to browse Web pages and append notes.

2. Annotation by sketching chemical diagrams. A typical use is JSME (for which separate help is available). Watch this space.

3. Voice and text-based notes. For example, Siri-to-chemical structure conversion.

10. Help with the chemistry. Please consult your tutor in the first instance, or ask after the lecture.

The HTML/CSS/JS source code for these notes has been Tidied/Beautified using this site. See also here. If you are interested in how the effects in these notes were achieved, please contact me.

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Organic Pericyclic Reactions

Five second year lectures by

Henry Rzepa (rzepa@imperial.ac.uk, Room 169, C2)

Department of Chemistry, Imperial College London.

DOI: http://doi.org/10042/a3uxp

Podcasts: iTunes or RSS

eBook for iPhone/iPad

eBook for Kindle

iTunesU for iPad†

iTunesU for Desktop

Annotations

Blog-stories‡

Twinned course: Conformational analysis

Other texts:

1. "Organic Reactions and Orbital Symmetry", T. L. Gilchrist and R. C. Storr, 2nd Ed., CUP 1978, contains many examples of all kinds of pericyclic reactions together with theoretical explanations. The book is out of print, and difficult to get hold of nowadays.

2. An OUP Primer "Pericyclic Reactions" by Ian Fleming (1998) is an excellent revision text: ISBN 0-19-850307-5, £16.99

3. "Pericyclic Reactions- a Textbook", by S. Sankaraman, Wiley-VCH, 2005. ISBN 3527314393. Contains many examples.

4. An article published in J. Chem. Education (2007) telling a synoptic story in this area (DOI: 10.1021/ed084p1535)

5. The original, and still readable, reviews by Woodward and Hoffmann (DOI: 10.1021/ar50001a003 or 10.1002/anie.196907811)

6. A short 200 year perspective on WH's impact on organic chemistry

The lectures are based on the material here rather than the texts above. These pages also contain many molecule/transition state models (benchmark 1) and surfaces (benchmark 2), which can be viewed on Desktop-type Web browsers (Firefox-26, Safari-7 or Chrome-34; Internet Explorer is compatible only for Windows 8.X) or Tablets (see tablet project).

‡These sections contain expanded stories in the form of a blog, and may be consulted for background, but are not examinable. Other fun and games can be found flat-packed, as a Valentine Special, the height of fashion, as 3D-printed objects (order here) or as a Möbius race-track. This material is also not examinable. †iTunesU material can also be loaded on Android devices.

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Historical Background.

Prior to the 1960s, organic reactivity was thought to be dominated by factors which included:

- the relative stability of reactant and product (i.e. thermodynamic control)

- the aromaticity of either the reactant or the product.

- The early/late nature of the transition state (the Hammond postulate, kinetic control).

- geometrical effects such as strain, steric interactions, hydrogen bonding, neighbouring group effects (entropy)

- electrostatic effects such as the polarity of functional groups (e.g. the carbonyl group)

- more of which in the follow up lecture course on conformational analysis

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During the course of the synthesis of vitamin B12 in the early 1960s, Robert Woodward concluded (see Chem. Soc. Special Publications (Aromaticity), 1967, 21, 217 for the full story) that none of the above factors could rationalise the following reaction. It was thought at the time using simple molecular models (the quantitative aspect of which was pioneered in 1951 by another great organic chemist and Nobel prize winner, Derek Barton) that the product was predicted to be J and that H would be more sterically demanding and hence less likely to form. It turned out the opposite was true.

A new explanation was developed based on 'stereoelectronic' factors, i.e. recognising that the three-dimensional properties of the electrons and their phase relationship could dominate the other factors listed above. This theory of stereoelectronic control of pericyclic reactions was derived using an approach known as the conservation of orbital symmetry, together with the theoretician Roald Hoffmann. Woodward died before the Nobel prize was awarded to Hoffmann (and Fukui) for this work (published in J. Am. Chem. Soc., 1965, 87, 395. The work was reviewed here). The recognition that stereoelectronic factors (more accurately the three dimensional properties of the molecular wavefunction) can be critical to explaining reactivity has had an enormous impact on understanding organic chemistry (see Introduction to Stereoelectronics in 3rd year).

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Modern Molecular Modelling

Since the original work in the 1960s, modern computer-based methods of molecular modelling allow us to investigate the original assumptions about which isomer might be expected to form. Quantitative models of both products can be readily constructed, and their relative energies calculated using a variety of methods. In this case, both so-called "Molecular Mechanics" and "Quantum Mechanics" methods suggest that both isomers are in fact fairly similar in energy. Another Nobel prize winner, John Pople, was awarded his prize for developing the Gaussian program, one of the best known of the molecular modelling systems, and one which has been crucial in quantifying aromaticity and creating accurate models of reaction transition states and potential energy surfaces.

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Definition of Pericyclic Reactions.

A pericyclic reaction is one in which bonds are made or broken in a concerted cyclic transition state. A concerted reaction is one which involves no intermediates during the course of the reaction (left). A stepwise and therefore non-concerted and non-pericyclic reaction is shown with a discrete intermediate (right).

Intrinsic Reaction coordinate (IRC) → → → → → → → → →

Understanding pericyclic reactions therefore involves understanding the transition states that control them.

Pericyclic reactions have certain characteristic properties, although as usual it is not difficult to find exceptions to all these rules.

1. There is no nucleophilic or electrophilic component. This means that in the arrow pushing sense, there is no beginning and no ending for the arrows, and the arrow pushing can occur in either a clockwise or anti-clockwise direction.

2. Normally, no catalyst is need to promote the reactions. However, many transition metal complexes can catalyse pericyclic reactions by virtue of d-orbital participation. Lewis acids also catalyse many forms of pericyclic reactions, either directly, or by changing the mechanism of the the reaction so that it becomes a stepwise process (ie the right hand diagram above) and hence no longer a true pericyclic reaction.

3. Pericyclic reactions normally show a very high stereospecificity.

4. Pericyclic reactions can be frequently promoted by light (denoted hν in the text) as well as heat (denoted Δ in the text). Normally, the stereochemistry under the two sets of conditions is different, and it was (originally) thought invariably opposite. Current thinking about the photochemical route is more complex!

5. Pericyclic reactions can occur in the gas phase with no solvent. There is a relatively small solvent effect on the rate of reaction (unless the reactants themselves happen to be charged, ie carbonium or carbanions). Quite recently, the use of water to accelerate pericyclic reactions (by perhaps a factor of 10 to 100) has been much investigated, but the acceleration is largely due to the formation of hydrogen bonds specific to the transition state.

6. It has very recently been shown that it is possible to influence pericyclic outcomes using quite literally mechanical stress (Mechanochemistry)

7. The reactions can be accelerated by the use of pressure for those involving a substantial decrease in volume. Catalysts ("molecular containers") also exist which provide suitable "cavities" for promoting pericyclic reactions such as cycloadditions.

8. Unlike nucleophilic/electrophilic reactions, pericyclic reactions are unusual in that surprisingly few enzymes which catalyse them are known. Artificial catalytic antibodies ('abzymes') can be created which can perform this feat, "Diels-Alderase" may do this for cycloadditions and Chorismate mutase does do this for the Claisen rearrangement, and they act via points 5 and 7 above.

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Principal Categories of Organic Pericyclic Reactions.

Here we make no attempt to describe the rich variety of inorganic reactivity that can also be described as pericyclic. There are four major organic categories covering a very wide scope of organic and organometallic chemistry, and which form a rich basis for understanding the more subtle aspects of synthesis and organic chemistry.

Major Categories

Before dealing with real pericyclic reactions, we should exclude bond-shifting isomerisations (as below, a relatively slow process, ~ms) or resonance (as in benzene, an extremely fast process, ~fs). At least one σ bond has to make or break for a pericyclic reaction proper.

1. Electrocyclic Reactions.

An electrocyclic reaction involves the concerted formation of one σ bond between the two ends of a linear conjugated π system, or the reverse reaction in which one σ bond is broken to produce a linear conjugated system. In these definitions, by 'conjugated', we mean a system of C-C multiple bonds, or of lone pairs.

2. Cycloaddition and Cyclo-elimination reactions.

A cycloaddition reaction involves the concerted formation of two or more σ bonds between the termini of two or more conjugated π systems. The reverse reaction involves the concerted cleavage of two or more σ bonds to produced two or more conjugated π systems.

The last example above is a three-component π2s + π2s + π2s cyclo-elimination reaction. For the specific case where formation or cleavage of two σ bonds occurs at a single atom, the reaction is called a Cheletropic reaction.

3. Sigmatropic Reactions.

A sigmatropic reaction involves the concerted migration of an atom or group from one point of attachment to a conjugated system to another point of attachment, during which one σ bond is broken and one σ bond is made. A sigmatropic reaction can be classified according to the length of the group that migrates, and the length of the backbone along which it migrates;

4. Ene (Group transfer) Reactions.

A general category which involves the formation and cleavage of unequal numbers of σ bonds in a concerted cyclic transition state. The top right example shows part of the mechanism for transforming a carboxylic acid to an acyl chloride using oxalyl chloride (three bonds broken, one made). This reaction also has features of a cheletropic elimination (above). The last example (bottom right) is of some recent interest (DOI: 10.1038/nature07010), involving the preparation of hydroxycarbene and its remarkable stabilization by deuterium isotope effect inhibition of the hydrogen tunnelling that is thought to be responsible for the very short lifetime of the undeuterated species (2 hours at 11K for the hydrogen version, 2000 years for the deuterium, an isotope effect of about 9 million!).

All these examples are 6-electron/4n+2 thermal processes.

Minor Categories

5. Multiple personality pericyclics.

A newly identified type of pericyclic reaction is the so-called bispericyclic, which simultaneously sustains the characteristics of two or more separate pericyclic reactions. Originally reported as the mechanism for the dimerisation of cyclopentadiene, it is now thought to be more common than previously thought. This has simultaneous characteristics of both a π2s + π4s and a π4s + π2s cycloaddition (they are not the same!) as well as a [3,3] sigmatropic shift. You will encounter this reaction in the third year molecular modelling lab

Another pericyclic type with multiple-personalities involves cyclopropane rings, which are often regarded as honorary alkenes. Should this be regarded as closer to an electrocyclic reaction of a triene (as above, with the cyclopropane acting an an alkene) or as a [1,5] sigmatropic rection (with the cyclopropane acting as a single bond)? This can also be regarded as a manifestation of homo-aromatic transition states (see later).

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Theoretical Explanation.

Our story starts with Évariste Galois (1811-1832) who founded the theory based on the symmetries of permutations which we now know as group theory. The original explanation of Woodward and Hoffmann based on the nature of the highest occupied molecular orbitals was formalised with the help of Galois' group theory by Longuet-Higgins and Abrahamson (DOI: 10.1021/ja01087a033, see also 10.1021/ja01087a033). This involved generating a so called orbital correlation diagram for the reaction under consideration, and then carrying out the reaction in such a manner that the group theoretical symmetries of the reactant and product orbitals matched exactly. Such an approach, whilst theoretically more rigorous, is not readily applicable to the majority of more complex reactions which have no formal symmetry. Two much simpler methods have been subsequently outlined which avoid this problem. The first these, based on transition state aromaticity, will be expanded in more detail, whilst the second (based on frontier orbitals) will only be described briefly in the next lecture.

1. Conservation of Orbital Symmetry (Longuet-Higgins and Abrahamson)

Let us first define the symmetry properties of a 1s and a 2p orbital with respect to a plane of symmetry or an axis of symmetry as shown below;

One can take this one step further by considering the symmetry properties of molecular orbitals formed by the overlap of two or more atomic orbitals;

MOs formed from two overlapping σ orbitals:

MOs formed from two overlapping p-orbitals (σ bonds):

MOs formed from two parallel overlapping p-orbitals (π bonds):

We can now use these basic orbitals to construct the relevant molecular orbitals for two interconverting molecules, cyclobutene and butadiene, with the purpose of following how these two sets of orbitals change when one molecule is converted into the other. Note particularly that we need only construct the MOs explicitly involved in the reaction; most of the σ framework remains unchanged and no orbitals derived from this need to be considered:

(click on the diagrams above or below to see the actual molecular orbitals)

In order to interconvert cyclobutene and butadiene, the four MOs labelled ψ_1, ψ_2, ψ_3, ψ_4 must be converted into ψσ, ψπ, ψπ*, ψσ*. There are two stereochemically distinct ways in which this might be accomplished;

Conrotation:

Disrotation:

This enables a correlation diagram for the reaction to be constructed, according to the following rules: no two orbitals of the same symmetry can cross during the reaction, whilst orbitals of different symmetry can cross. The favoured pathway is the one which results in a product of the same electronic excitation as the reactant (green).

Pathways which result in the product being formed in a higher electronic state than the reactant are said to be "forbidden" (red).

Whilst this rule is normally followed fairly well for ground states, it can be overturned when for example steric or geometrical strain in the "allowed" pathway promotes the "forbidden" route. The situation is actually more complex for photochemical reactions, and much recent evidence suggests that the Woodward-Hoffmann rules are not always followed. These correlation diagrams can be generalised for any electrocyclic reaction with appropriate symmetry. However, correlation diagrams are less readily applied for reactions with no symmetry and a method more tolerant of broken symmetry is required. In the next section we will introduce such a method.

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Tabular Pericyclic Reaction Selection Rules

Condition

+ Electron count

+ Stereochemistry ⇒

Topology

≡ Lk

1: Heat (Δ)

4n+2

Suprafacial‡

Hückel

0†

2: Light (hν)

4n

Suprafacial‡

Hückel

0†

3: Heat (Δ)

4n

Odd antarafacial

Möbius

Odd

4: Light (hν)

4n+2

Odd antarafacial

Möbius

Odd

Diagrammatic Pericyclic Reaction Selection Rules

Frost, Musulin and Zimmermann diagram (1965)

‡Or even antarafacial †Or even Lk

Selection rules derived from Transition State Aromaticity (Dewar and Zimmermann)

Dewar and Zimmerman independently noticed that the symmetry properties of the molecular orbital correlation diagrams for pericyclic reactions are very similar to those obtained using eg Hückel theory for aromatic molecules. For example, the MO diagram for the electrocyclic conversion of hexatriene to cyclohexadiene is remarkably similar at its transition state to the ground state MOs of benzene;

The rules work on the premise that favourable pericyclic reactions will proceed via an aromatic transition state. There are in fact two basic kinds of relevant aromaticity that differ fundamentally in their symmetry/topological properties. Depending on whether the reaction is promoted by heat or light (Δ or hν) we can divide the rules into a total of five categories.

1. Thermal (closed shell electronic state) with ~plane of symmetry/suprafacial and no twist: Hückel Aromaticity and Lk=0.

The suprafacial mode orbital correlation diagram for hexatriene can be generalised by reference to benzene, the archetypical aromatic molecule. The benzene molecule has suprafacial π-conjugation, deriving from a plane of symmetry. This means that the π-electron density in benzene is cyclically continuous along either the top OR the bottom face of the molecule and reflects symmetrically in a plane of symmetry bisecting the benzene. In mathematics, this type of topological object is more generally known as a two component torus link‡ with a linking number Lk of zero.

Benzene is particularly stable (=aromatic) because the cyclically conjugated π electrons all occupy stable doubly-filled molecular orbitals for which the total π-electron count conforms to the equation 4n+2; the Hückel rule, where n = 0, 1, 2 etc (a rule incidentally not actually formulated by Hückel but by the organic chemist William von Doering, see DOI: 10.1021/ ja01146a537).

If the transition state for the pericyclic reaction has the same π-electron density suprafacial topology, it is said to be a Hückel system. This is in honour of Erich Hückel who first indicated why a molecule such as benzene should be especially stable (and also, as it happens, was also the first to formalise the separation of σ and π electrons). It follows the same 4n+2 rule as for benzene, but this time counting the electrons involved in the reaction rather than just the π-electrons in the aromatic ring.

The advantage of this approach is that aromaticity is quite stable to perturbations to the symmetry (benzene rings in e.g. cyclophanes for example can be bent by up to 30° and still retain their aromaticity as evidenced by e.g. NMR).

So we conclude: closed shell pericyclic reactions will proceed all suprafacially via Hückel stereochemistry if the electron count corresponds to 4n+2. Hence this rule can now be applied to unsymmetric pericyclic reactions, which of course are by far the most common.

Student question: Can a transition state be so stabilised (by aromaticity) that it becomes an intermediate in its own right? A: See

2. Photochemical (open shell) with ~plane of symmetry/suprafacial and no twist: Hückel Aromaticity and Lk=0

Some time after Hückel, it was shown that the excited (triplet) electronic state of cyclic suprafacially conjugated π system created by (photochemically) promoting one electron from a doubly occupied orbital into a higher energy molecular orbital to produce what is called an open shell molecule is associated with aromaticity only if the π-electron count is 4n rather than 4n+2. An example of such an open shell aromatic molecule is the triplet state of cyclobutadiene.

Applying the same analogy as before, we infer that open shell pericyclic reactions (which normally means photochemically activated) will proceed suprafacially via Hückel stereochemistry if the electron count corresponds to 4n. The most modern approach does not use transition states to infer the stereochemistry for the photochemical reactions, but another feature in the potential energy surface(s) known as the conical intersection, with normally the same stereochemical conclusion.

3. Thermal (closed shell electronic state) with 1 twist (axis of symmetry/one antarafacial mode): Möbius Aromaticity and Lk=1

The antarafacial stereochemical mode associated with the orbital correlation diagrams is said to resemble Möbius topology, after August Ferdinand Möbius, who invented the famous strips (as did Johann Benedict Listing). An antarafacial mode can be formed by taking a cyclic alkene "strip" and giving its π-electron system a 180° (half) twist (and in doing create a two-fold axis of symmetry in the resulting molecule). Edgar Heilbronner in 1964 speculated theoretically (no such molecules were then known) that such a twisted system would be a closed shell molecule if it contained 4n conjugated π electrons doubly occupying 2n MOs. It was later shown that it would also be aromatic! It is very recently recognized (DOI: 10.1039/b810301a) that topological analysis of the electron density derived from these 4n-electrons indicates it to be a topological object known as a single-component torus knot‡, with a linking number Lk of one (the specific name of such a knot is actually an unknot). As might be expected of an object with only a two-fold (C_2) axis of symmetry, it has disymmetric chirality.

The first explicit example of a Möbius molecule was suggested in 1998 as being the cation C_9H_9+ (which has 8 cyclically conjugated π-electrons). It is a 4n system, where n=2 and its 1H NMR suggested it was indeed aromatic, from which it was inferred as being Möbius. In 2003, a crystalline Möbius annulene was first made (DOI: 10.1021/cr030092l) and the axis of symmetry was finally revealed. Quite a number of Möbius systems have been identified from 2006 onwards.

So, using the same analogy as before, thermal pericyclic reactions will proceed with one antarafacial component via a Möbius aromatic transition state if the electron count corresponds to 4n.

4. Photochemical (open shell) with 1 twist (axis of symmetry/one antarafacial mode): Möbius Aromaticsity and Lk=1

Just as photochemical (excited state) Hückel systems conform to a 4n-electron rule, so photochemical Möbius systems conform to a 4n+2-electron rule. As before, we nowadays use a conical intersection rather than a transition state geometry to infer the rule using quantum mechanics.

5. Systems with 2 or more twists (axes of symmetry/more than one antarafacial mode): Higher order Möbius Aromaticity (Lk > 1).

In 2005, it was realised that topological objects with two twists were also interesting. Whilst largely beyond the scope of these lectures, it is worth noting here that two twists in cyclically conjugated π-electrons give a Möbius aromatic molecule which again conforms to the 4n+2 rule, but this time the molecule has disymmetric chirality which is associated not with a plane of symmetry but with (three or more) axes. Its electron density gives rise to a topological object known as a torus link with linking number Lk of 2‡. The chemistry of chiral aromatic molecules (before 2005 regarded as a chemical oxy-moron) is now rapidly expanding and around 30-40 molecules with these features are known. And again, one can draw an analogy with pericyclic transition states. This will exhibit two antarafacial components (the number of these are formally equal in value to the linking number). For (optionally) more details, see here or the blog.

(Optional) Pericyclic Reaction Selection Rules based on Fukui's Frontier Orbital Method

(This approach is optional and is intended for use in tutorials). This involves using the principles of quantum mechanics to generate the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) for the reactant(s). The formation of the new σ bond must occur by appropriate overlap of the nodes of these orbitals. If only one σ bond is forming, as in an electrocyclic reaction, then only the overlap of the HOMO of the reactant is considered. Such overlap can occur in one of two fundamental ways; The suprafacial mode involves each component of the new σ bond being formed from the SAME face of the reactant π system. See DOI: 10.1016/S0040-4039(01)83901-0.

The antarafacial mode involves a 'twisting' of the orbitals so that the two components of the new σ bond come from OPPOSITE faces of the reactant π system. If two or more σ bonds form during the reaction, as in cycloaddition reactions, then the overlap of the HOMO of one reactant with the LUMO of the second reactant must be considered. For simple systems, the form of the HOMO and LUMO is not difficult to remember. For more complex systems, explicit calculations have to be carried out and the Frontier Orbital method becomes more difficult to apply. The advantage of the "FMO" method is that it can be expressed quantitatively in terms of the magnitude of the coefficients involved, and can hence be used to predict regioselectivity etc.

(Optional) The Modern Approach involving the location and molecular dynamics of transition states and conical intersections in the potential energy surface(s).

The next level of theory beyond the FMO method involves the explicit location of the pericyclic:

1. transition state for a thermal reaction

2. conical intersection for a photochemical reaction

using quantum mechanical potential energy surfaces and dynamics. You will get a chance to try this out in 3rd year computational labs.

‡The first attempt to theoretically derive the periodic table of elements was made in 1867 and was based on knots, not quantum mechanics which of course had not yet been invented! Even more spooky, knots are now the basis of string theory, which attempts to explain the inner structure of all fundamental particles. Explore links and knots here or here.

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Eight Examples Of Electrocyclic Reactions.

1. We start at the beginning. In 1958, Vogel reported (DOI: 10.1002/jlac.19586150103) unexpected stereochemistry for ring opening of a cyclobutene, as shown below. Two electron arrows are involved and hence they are 4n electron systems (n=1).

Intrinsic reaction coordinates

Ring opening of a cyclobutene

Ring closing of a butadiene

According to the rules shown in the previous lecture, thermally the reaction will proceed via a Möbius aromatic transition state involving one antarafacial component. Both ester groups will rotate in the same direction (conrotation). The process in this case does not preserve an axis of symmetry exactly, but only approximately. This can also be (optionally) illustrated via the Frontier orbital (HOMO) approach.

In order to form a new sigma bond, the HOMO of the butadiene fragment must rotate in the sense shown, one node coming from above the plane of the molecule, the other from below (ie antarafacial). A 3D printed model of this orbital is available for inspection (reminder: show the students the model!).

2. Under photochemical conditions, a 4n reaction is predicted to proceed via a Hückel aromatic transition state with suprafacial bond formation and a (presumed) plane of symmetry, as for example;

The sense of this can again be seen from the frontier orbital (normally the LUMO but in the excited state occupied by a single electron, and hence effectively the HOMO). A 3D printed model of this orbital is available for inspection (reminder: show the students the model!).

A more modern approach to understanding photochemical reactions is to locate the conical intersection rather than the transition state.

This reveals that the suprafacial specificity is retained but that the plane of symmetry is not.

3. Opening of the cyclopropyl cation involves only one electron arrow, and hence the number of cyclically conjugated electrons is 2 (4n+2, n=0). Under thermal conditions, this will go via a Hückel aromatic transition state involving a suprafacial component, which has the effect of rotating both methyl groups outwards in opposite directions (disrotation) and in the process preserving a plane of symmetry.

Note that in the transition state model, the leaving group (protonated water in this model) has not entirely departed before the electrocyclic ring opening starts. In reality, the SN1 solvolysis and the electrocyclic pericyclic may in fact be synchronous with each other, rather than comprising two separate and distinct steps.

Both together constitute a single concerted process, a sort of mechanistic morpheme taking the form of a solvolytically-assisted pericyclic reaction.

4. Where hetero-atoms are involved, the lone pair counts as two electrons. Thus the ring opening of aziridine is a 4 electron process (=4n) with one antarafacial component, proceeding via a Möbius aromatic transition state with both methyl groups rotating in the same direction (conrotation) preserving an (approximate) axis of symmetry

5. 4n+2 (n=1) examples of steroidal reactions which can only be rationalised on the basis of the selection rules;

In fact, when first discovered in 1961, the origins of this stereochemistry rather baffled the authors (Havinga and Schlatmann, DOI: 10.1016/0040-4020(61)80065-3), and the effect was not followed up.

Another in the category of missed Nobel prizes was the reaction Corey reported in 1963, where what is described as a key element in the synthesis of dihydrocostunolide was the ring opening shown below (10 in the article).

This is a 4n+2 electrocyclic photochemical ring opening which proceeds antarafacially with conrotation, followed by a thermal 4n+2 recyclisation proceeding suprafacially with disrotation. Had either of these pairs of authors spotted the stereochemical significance and commented on it, we might now be talking about the Havinga and Schlatmann or the Corey rules rather than the Woodward-Hoffmann rules!

6. One important aspect when counting electrons is to include only the cyclically conjugated system. In the example below (DOI: 10.1002/anie.196708701) for one valence-bond conformational isomer (with a Cs plane of symmetry and hence formally at least being a 4n-electron Hückel antiaromatic) of a [16] annulene, the arrow pushing gives rise to two independently cyclic six electron (4n+2) electrocyclic reactions, and the electrons in the central double bonds are NOT counted in the process, since they are simply spectators and hence 4 of the 16 electrons do not participate (in what would otherwise be a forbidden π4s+π4s cycloaddition). The two outer rings are 4n+2 Hückel-aromatic transition states, the central ring is a Hückel 4n-electron anti-aromatic spectator. In fact, if the two electrocyclic reactions proceed consecutively rather than concurrently, the Hückel anti-aromaticity in the central ring is also avoided and this is actually what happens.

If the [16] annulene is drawn as a different valence bond isomer, it can have a different conformation because the central C=C bond changes to a C-C bond and rotation about this bond can now occur at room temperatures. This new conformation has a C_2 axis of symmetry instead of a plane, and so 4n-electron Möbius aromaticity takes over for both the annulene and the transition state for cyclisation, and one now gets a π4a+π4s cycloaddition with one antarafacial component in the central region. This time the dienes and their 8 electrons at each side are simply spectators (in what would otherwise constitute two dis-allowed conrotatory 4n+2 electron electrocyclisations). The central ring is a 4n-electron Möbius-aromatic transition state, the two outer rings are 4n+2-electron Möbius anti-aromatic spectators. In part because this mode has two (spectating) anti-aromatic rings, it is 14.8 kcal/mol less stable than the previous Hückel mode.

4n+2 Hückel:

Plane of symmetry

4n Möbius:

Axis of symmetry

A related story for the smaller [14]annulene is told on the blog, which also has unexpected outcomes.

7. Carbanions contribute 2 electrons to the total count, the reaction proceeding suprafacially (DOI:10.1016/0040-4020(78)80226-9)

8. Finally, as a conundrum, think about the following ring opening and whether it proceeds via a Hückel or a Möbius transition state?

This last example apparently contains a logical contradiction in being two different reactions simultaneously. For an explanation, go see the article here or the blog:

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Eleven Examples Of Cycloaddition/Elimination Reactions.

1. The most common example is the Diels Alder cycloaddition (for a review, see here). Two π systems are involved, one contributing 4π electrons, the other 2π electrons. The total count is 6 (4n+2, n=1) and since the reaction is thermal, it must proceed via Hückel topology involving only suprafacial components (or, hypothetically, two antarafacial components, but this is geometrically impossible here).

These are considered as follows. Each π system forms two new σ bonds. These two new bonds can either form on the SAME face of one π system (suprafacial) or from opposite faces of one π system (antarafacial). A system of nomenclature has been developed to describe this. Hence the system below is classified as a π4s + π2s cycloaddition (i.e. both bonds forming on the bottom face of the diene = π4s and both bonds forming on the top face of the alkene = π2s, the so-called exo form). An isomer in which the bonds form to the bottom face of the alkene is also π2s (the endo isomer) is actually predicted to be slightly more stable (as a transition state) than the exo form. For a brief discussion of the application of frontier orbital method to cycloaddition reactions, see here.

endo

exo

2. An example of an enzymically catalysed Diels-Alder reaction is the unique enzyme extracted from Alternaria Solani which catalyses a π4s + π2s cycloaddition in prosolanapyrone (III) with very high exo-selectivity (the normal uncatalyzed selectivity is endo). The structure of this enzyme was reported here.

This highly active (indeed controversial, see here) area includes discussion of Diels-Alderases, Theozymes, antibodies and Biosynthetic Diels Alder.

3. Diels Alder additions have also been observed catalysed within the cavities of certain organic crystal structures. In this example (10.1021/ja964198s) one molecule of cyclohexadiene is encapsulated inside a cavity formed from four ligand molecules, along with TWO molecules of ethyl methacrylate either side, one of which adds in Diels Alder fashion. The specificity for endo is enhanced by the crystal cavity.

Such reactions can also be catalysed using water as a solvent (10.1021/ja0010249), the catalysis arising in part due to specific hydrogen bonds which are strongest in the transition state.

4. This next example is a 4 electron (4n) cycloaddition reaction,

which proceeds photochemically (DOI: 10.1021/ja01030a066) via a Hückel topology (π2s + π2s). The ratio of all-cis (endo) to the exo form was unexpectedly found to be 1.3:1, indicating attraction rather than repulsion between the methyl groups. Photochemical reactions are nowadays recognised as being controlled by the properties of a conical intersection (the lowest energy point at which the ground and excited state "touch") rather than a transition state, although the selection rules derived earlier are in fact often adhered to.

Thermally, the dimerisation of e.g. ethene is predicted by the selection rules to proceed as a π2s + π2a, the subscript a indicating an antarafacial component must be present on one alkene. However, there is a problem; an antarafacial mode implies a Möbius like twisting of 180° in the π system of the ethene, but ethene has only two carbons and cannot be twisted so much! A quantitative model indicates that only about 130° of twisting can actually be induced, of which about 80° occurs on one ethene and 50° occurs by twisting one ethene with respect to the other. Strain is also relieved by forming the two bonds at different rates.

The trans alkene shown below has sufficient driving force to actually indulge in this rather twisted transition state. Note that only the two strained trans double bonds react; the more stable cis double bonds do not participate in the reaction, although they do help stabilize the transition state. See here for the original report, and here for an update which implicates some contribution from biradicals in the process, as do high level calculations.

5. A more common example of a presumed π2s + π2a reaction is the reaction between a ketene (or keteneimine) and alkene;

The antarafacial component is present only in the transition state, and it has the effect of giving the more sterically hindered product (see DOI: b3sxdz). It was noted above that one way of relieving strain induced by an antarafacial component is to make the two forming bonds of unequal length. In this example, this inequality allows the two large groups (t-butyl and phenyl) to avoid each other in the transition state, even though this is not possible in the final product. At the transition state, this isomer shown here is 3.0 kcal/mol lower in free energy than the unformed C-Ph epimer.

In extreme of bond asymmetry, which the ketene above is tending towards, this corresponds to forming a carbocation and carbanion. This of course is now a stepwise rather than concerted reaction and is no longer a pericyclic process. Many 2+2 cycloadditions are thought to proceed in this manner, especially in more polar solvents which stabilise the intermediate zwitterions (and which non-polar solvents suppress). In other systems, such asymmetry corresponds to the formation of so called "biradical intermediates", and recent evidence suggest these routes may be more common than hitherto suspected!

6. As before, lone pairs count as two electrons, making the next example a six electron suprafacial system; π2s + π4s. The regiochemistry cannot be explained by the pericyclic selection rules; it is instead determined by more complex orbital overlaps.

7. Ten electrons (4n+2, n=2) can also participate in thermal cycloadditions (DOI: 10.1021/ja00853a063) such as the reaction between tropone (six electrons) and cyclopentadiene (four electrons). The reaction is suprafacial on both the 6 and the 4 components (π4s+π6s):

However, we can again see an incursion of unequal bond lengths at the transition state, and this might be a feature of all cycloadditions with 10 or more electrons.

8. The largest number of electrons in a thermal cycloaddition has been proposed as 16, in a π2s + π14a reaction (See DOI: 10.1016/0040-4039(81)80058-5). Since 16 electrons = 4n (n=4) this requires one antarafacial component.

One point to note is that the antarafacial component could in principal occur on either alkene, but in practice the geometrical distortion is such that either the more strained or the larger component bears the antarafacial mode. This system is also likely to feature unequal lengths of the forming bonds.

9. Synoptic examples 1: A recent (and it has to be said controversial) example is the claimed isolation of cyclobutadiene using the reaction shown below. Molecule 1 is inserted into a (calixarene) cavity and photolysed. It first of all undergoes a suprafacial electrocyclic reaction to give 2, and photolysis at a different wavelength then induces a π2s - π2s cyclo-elimination reaction to give the cyclobutadiene and a molecule of carbon dioxide.

This system was then subjected to X-ray analysis to determine the structure of the cyclobutadiene. The controversy is over whether the second photolysis did take place at all, or if it did, whether a thermal π2s - π4s cycloaddition reaction occurs rapidly enough to destroy the cyclobutadiene and reform compound 2.

10. Synoptic examples 2: The formation of endiandric acid (DOI: 10.1039/C39800000162) involves the creation of eight chiral centres (2**8 = 256 isomers!) from a simple linear polyene precursor. This consists of a sequence of pericyclic reactions (a pericyclic cascade or tandem reaction) to give the four membered ring system. Nicolaou (DOI: 10.1021/ja00384a080) unravelled the biomimetic pathway.

A subsequent intramolecular π2s + π4s Diels Alder cycloaddition gives the final product (note how in this transition state, one of the forming C-C bonds forms at a significantly faster rate than the other, it being "tethered" by the adjacent five membered ring, whilst the other end is more floppy).

The bonds formed in this overall sequence can be inspected by clicking on the diagram below:

Eight stereogenic centres are formed from the starting achiral polyene, implying that 128 stereoisomers (+ their 128 enantiomers) could be formed. In fact, the pericyclic selection rules reduce this number (not completely down to one of 128, since the selection rules do not specify whether the Diels-Alder step is endo or exo). The only isolated form has the relative stereo-chemistries shown in the model above. But in the absence of any additional chiral auxiliary, this stereoisomer is formed as a racemic mixture of it, and its enantiomer.

11. This is another apparent contradiction:

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Ten Examples of Sigmatropic Reactions.

1. H Shifts: There are two different types of sigmatropic reaction, a) those that involve the migration of a hydrogen atom and b) those that involve a carbon or other atom. In the former category, the hydrogen atom can migrate either suprafacially or antarafacially across the conjugated system, leading to Hückel or Möbius topology for the transition states;

2. C Shifts: Something different can occur when a carbon migrates.

The configuration at the migrating centre can be either retained (= suprafacial mode = Hückel topology) or inverted (= 1 antarafacial mode = Möbius topology). Note that Möbius transition states are relatively common in this class because there is often little strain involved in inversion of configuration at a carbon.

3. [1,5] Hydrogen shift: The most common category of hydrogen shift involves a so called [1,5] hydrogen sigmatropic shift (n=1 in the above diagram). A practical example of this reaction involves the preparation of Chiral ethanoic (acetic) acid (CHDTCO_2H, where D= 2H and T=3H) which has long been an invaluable tool for elucidating biochemical mechanisms, but whose synthesis has been long, difficult and in low yield. Recently a new and particularly efficient route to this molecule has been developed (DOI: 10.1021/ja992498e) based on the reaction shown below, which involves 6 electrons, and hence falls into the 4n+2 thermal Hückel category. Heating the reactant gave a single product Z only if the alkyl group R= t-butyl. Smaller alkyl groups gave Z along with an isomer. Z was converted to chiral ethanoic acid (along with the three other products shown) by the sequence of three reagents shown. With R=tBu only a single product is formed, whereas with smaller R groups two compounds are formed.

The reason for this can be seen more clearly when quantitative models of each transition state are constructed. The Favoured form involves migration of the hydrogen suprafacially along the top face of the diene. The methyl group (on the carbon the H is leaving) points inwards in the direction of the migrating H and the R=tBu group points outwards, out of harms way. This transition state has a modelled energy ~5 kcal/mol lower than the unfavoured form, in which the H migrates (also suprafacially) along the bottom face of the diene, via a rotamer (of the C_1-C_2 single bond) of the original transition state, in which now the R=tBu group now points inwards, increasing the steric congestion. The result of the H migrating along the top face is to transfer the (S)-C_1 chirality to (R)-C_5 chirality with complete selectivity. Any migration along the bottom face would have transferred (S)-C_1 chirality to form (S)-C_5 instead, resulting in loss of enantiomeric (R)-purity for the ethanoic acid. It goes without saying that any contamination by antarafacial migrations of the H group would also have had this effect!

Suprafacial/top

suprafacial/bottom

4. Another illustration of [1,5] hydrogen shifting can be seen in cyclopentadiene: The structure of this species implies that the 1H nmr spectrum should contain a triplet at about δ4 ppm corresponding to the sp^3 protons and more peaks at about δ 5-6 corresponding to the sp^2 protons, the ratio being 1:2.

In fact, the room temperature spectrum shows only one peak at about 4.8 ppm. The reason for this is that a series of successive [1,5] hydrogen shifts is occurring so quickly that only the 'averaged' proton position is manifested in the nmr spectrum. Slowing down the exchange by cooling to about -50°C produces the expected spectrum described above! Many nmr spectra are affected by these so called 'degenerate' pericyclic processes, also called "ring whizzing".

5. [1,4] Hydrogen shifts. These can take place from anionic or cationic conjugated systems.

The 4n-electron cationic system proceeds antarafacially, but the 4n+2-electron anionic systems go suprafacially (with a barrier about 12 kcal/mol lower in energy).

cationic/antarafacial

anionic/suprafacial (bottom)

6. [1,3] Carbon Shifts: The next example illustrates a [1,3] migration (DOI: 10.1016/S0040-4039(01)88223-X )

This involves 4 electrons, is hence a 4n process requiring Möbius topology, and this can be most easily achieved by inverting the configuration of the migrating carbon atom. If a model of this reaction is constructed, one can see that the configuration of the migrating sp^3 carbon is indeed inverted.

In reality, [1,3] carbon shifts may be more complex, a fair number of them proceeding via biradical intermediates, and with the stereochemical consequences controlled by reaction dynamics rather than pericyclic aromaticity. See DOI: 10.1039/b711494j

The photochemical equivalent of the reaction above is predicted to require Hückel topology (hν/4n = supra) and the conical intersection for this reaction indeed reveals this:

A cationic analogue, from the numbering, is classified as a [1,4] carbon migration.

Again, the electron count corresponds to 4n, and again inversion at the migrating carbon atom is required. In this example this inversion is actually directly illustrated by inspecting the nmr spectrum (DOI: 10.1021/ja01027a059 and 10.1021/ja00827a026). Three and only three distinct methyl peaks are observed in the 1H nmr spectrum. This would only occur if [1,4] migration is fast, and also if inversion at the migrating centre were occurring, because this retains the individual identity of the two methyl groups Mea and Meb (i.e. Mea always overhangs the 5-ring). If retention at the migrating centre were to occur, the two methyl groups interchange their identity, and only two peaks would have been observed.

Shown below is the reaction coordinate for this methyl migration. The barrier is about 13 kcal/mol, which is what the NMR measurements indicate. However, there are two distinctly different events happening. In the region marked as IRC ± 8, we have a pericyclic reaction. In the region of IRC ± (8-15) we have a conformational process occurring. This latter will be discussed in the next lecture course! See also DOI: 10.1134/S1070428007080076

[1,4] cationic carbon migration

The ring walk

Thanks to Alex Genaev for the rhs image

7. The next carbocation homologue, a [1,6] cationic shift (3 arrows=4n+2) occurs with retention of configuration (=suprafacial) at the migrating centre. The starting cation is itself interesting, being a prime example of so-called homoaromaticity (homotropylium cation).

[1,6] shifts in homotropylium cation.

Retention (barrier 17.7 kcal/mol)

Inversion (barrier 38.6)

Thanks to Alex Genaev for the above images

8. [1,7] Shifts: This 4n-π-electron series explores the competition between the antarafacial mode being manifested via inversion at a single carbon, or antarafacial along a chain of atoms.

1. Thus a [1,7] Hydrogen shift can only occur antarafacially (see DOI: 10.1021/ja00287a058 and 10.1021/jo00248a029).

2. and shows also as [1,7] antarafacial hydrogen ring-whizzing in cycloheptatriene (the analog of the suprafacial H-whizz in cyclopentadiene)

but this process competes with a

3. [1,5] suprafacial hydrogen shift in the same molecule, which in fact is some 40 kcal/mol lower in energy!

4. A [1,7] Methyl shift can occur with antarafacial migration with retention at the methyl

5. Or with suprafacial migration with inversion at the methyl. This latter wins, being some 22 kcal/mol lower in energy.

9. [3,3] shifts: The next example is the one given in the introduction; the "Cope" rearrangement;

Here, an allyl group is migrating rather than a single carbon atom. The electron count is 6 (4n+2) and the reaction is thermally allowed via Hückel topology with suprafacial components, via a chair-like transition state.

In this category thare is also a (rare) instance of the transition state being so stabilised (by aromaticity) that it becomes an intermediate instead!

When an oxygen atom is involved, the reaction is called a "Claisen rearrangement". An enzymically catalysed sigmatropic reaction involves the Claisen type conversion of "chorismate" to "prephenate" by Chorismate mutase;

The story of frozen Cope reactions is told here. When hetero-atoms are involved, sigmatropic rearrangements involve odd numbers of atoms, as in this [2,3] rearrangement

For this reaction too, an enzyme catalysed mode is known (DOI: 10.1021/ja962257w).

10. The benzidine rearrangement was thought (DOI: 10.1021/ja00335a035) to proceed via a ten-electron [5,5] sigmatropic shift, suprafacially on both 5-atom groups, via a di-protonated species. The actual mechanism is now thought to be more subtle, proceeding through a transient π-complex, as first proposed by Dewar. The same mechanism also explains why PhNHOPh and PhOOPh do not exist, since the [5,5] sigmatropic has a very small barrier indeed.

The End

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu. 1 When compound 1 is heated, a transient intermediate 2 is formed, rapidly rearranging to two new compounds 3 and 4. An aqueous workup of this mixture, in which traces of acid were present, showed that 4 had been converted to 5. Suggest structures for compound 2-4, and mechanisms for all the steps in this sequence.

Answer

Qu. 2 When compound A is heated, carbon dioxide and benzonitrile (PhCN) are eliminated and the final observed product is the indole G. It is thought that the mechanism of the reactions proceeds via a series of intermediates B - F, the structures of two of which (D and E) are shown below. Suggest probable structures for the other species B, E and F and mechanisms for all the reactions. Pay attention to why both C and D give the same intermediate E, any selection rules that may relate to individual steps and the nomenclature of each step.

Answer

Qu. 3. a) When molecules 1 and 2 (E = CO2Me) are heated together, the transient intermediates 3 and 4 are formed, with the eventual isolation of 5 and 6 as the two final products. Propose structures for 3 and 4 and a mechanism for the formation of 5 and 6.

b) Propose structures for A and B and mechanisms for the following transformations.

Answer

Qu. 4 Photolysis of compound 7 in benzene as solvent produces the triene 8, which then decomposes thermally to give butadiene and tetralin (12), via it is thought the intermediates 9, 10 and 11. Propose and classify the mechanisms for these transformations, and suggest a structure for 11.

Answer

Qu. 5. a). Suggest a mechanism for the following reaction which explains the observed stereochemistry;

b). Propose a structure for 1 consistent with the spectral evidence and classify the type of pericyclic reaction occuring, paying particular attention to the expected stereochemistry of the product. 1H nmr includes the following; d 1.43 (3H, s), 1.52 (3H, triplet, J 1.5Hz), 3.76 (1H, multiplet), 5.71 (1H, multiplet), 5.73 (1H, double doublet, J 10, 1.5Hz), 5.79 (1H, doublet, J 10Hz), 6.74 (1H) + phenyl protons. No carbonyl peak is evident from the infra-red spectrum and no cyclopropyl group is present in 1.

Answer

Qu. 6. Tropylium tetraborate can be reduced with Zn/Hg to ditropyl [A].

Ditropyl is in equilibrium with an isomer, which when refluxed with an excess of the dimethyl ester of acetylene dicarboxylic acid (DMAD= MeO2C-CC-CO2Me) reacts to give a single adduct [B] with the following nmr properties; d 6.0 (4H, t, 4Hz), 4.05 (4H, broad singlet), 3.75 (12H, s), 1.2 (4H, double doublet, 3Hz, 2Hz), 0.9 (2H, triplet, 3Hz). When [B] is subjected to flash vacuum pyrolysis at 600 (FVP) two compounds [C] and [D] are formed. Compound [D] is stable and has the following nmr spectrum; d 7.62 (8H, symmetrical multiplet), 3.90 (12H, s). The 1H nmr spectrum for compound [C] includes the presence of vinylic protons (4H), but on standing these slowly disappear and a signal at d 7.37 (6H) due to benzene takes their place. Suggest possible structures for [B] - [D], paying particular attention to possible isomeric forms, the mechanisms of their formation and their nmr spectral properties. There is no need to propose a mechanism for the conversion of [C] to benzene.

Answer

Qu 7. a) Propose a mechanism for the following transformation, identifying any intermediates that might be involved;

b) The following transformation can take place via two alternative pathways, one involving intermediates 2 and 3, the other involving a single intermediate 4. When 13C label is introduced into the reactant, the product can be shown to have the label distributed as shown. Suggest possible structures for the intermediates 2-4, and on the basis of the labelling information, indicate which mechanistic pathway is actually followed.

Answer

Qu 8. When compound 5 is photolysed in heptane, a solution of "x" is formed. This solution shows the following nmr properties. At -76° complex multiplets in the 1H nmr spectrum are seen at δ 6.3-4.8 and at 3.3- 1.4 ppm. As the temperature is raised, both multiplets are broadened and portions of each multiplet move together and coalesce to a single multiplet at d 3.82 at a temperature of 78°. The integral of this coalesced multiplet is 1/6 of the total proton integral. On recooling to -76°, the spectrum returns to its previous appearance. If the solution is subjected to catalytic hydrogenation, compound 7 is one of the products. If the solution is heated to 98°, "x" then reacts to form a new compound 6 in which the two vinyl groups are specifically trans.

Suggest possible structure(s) for the unknown "x", paying particular attention to stereochemistry and the nmr behaviour. Suggest a conformational explanation for why 6 has trans stereochemistry (Hint: what must the most stable conformation of the precursor to 6 be and how would you estimate this quantitatively?)

Answer

Qu. 9. Classify the type of thermal reaction occuring in the sequences below, indicating clearly any stereochemical implications.

Answer

Qu. 10. Classify the type of (thermal) pericyclic reaction occuring for each of the eight steps shown below, showing clearly how many electrons are involved in each step, and discuss any obvious (or indeed less obvious!) stereochemical implications and nomenclature.

Answer

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 11. a) Propose a mechanism for the following transformation, including an explanation for the formation of two products and indicating the number of electrons involved in each step. Extrapolating from this explanation, suggest a related third product that might have formed, but as it happens was not detected with these particular substituents.

b) In the following sequence, the technique of flash vacuum pyrolysis results in the trapping of HNCO, HCN and a novel third product Z on a cold finger. The species Z shows at least one ir band in the region 2280 cm-1. When trapped with two quivalents of methanol, Z gives the product shown. Suggest possible identities for the two intermediates ³X and Y as well as Z, and mechanisms for all the reactions, including details of nomenclature for each step.

Answer

Qu 12. In the following sequence, suggest possible structures for the intermediates L, M and N, together with mechanisms and nomenclature for their formation. Discuss whether each step is formally allowed by the pericyclic selection rules for thermal reactions, or whether it requires the presence of traces of acid or base.

Answer

Qu 13. Suggest a nomenclature for the following three substrates;

Answer

Qu 14. When a mixture of hexa-2,4-dienol, CS2, KOH and prop-2-ynyl bromide is stirred for 12 hours at room temperature, the expected compound 1 is not isolated. Instead an oil "A" with the following spectroscopic properties is obtained; [[nu]]max 1646 cm-1, dH 1.70 (3H, d, J 6Hz), 2.23 (1H, t, J 3Hz), 3.73 (2H, d, J 3Hz), 4.84 (1H, dd, J 7, 8 Hz), 5.16 (1H, d, J 10 Hz), 5.27 (1H, d, J 17 Hz), 5.51 (1H, dd, J 8, 16.5 Hz), 5.72 (1H, dq, J 6, 16.5 Hz), 5.88 (1H, ddd, J 7, 10, 17 Hz). On heating to 180*C, compound 2 was isolated in 62% yield, via the presumed intermediate shown. Identify compound "A", suggest mechanisms for the subsequent reactions of 1, and assign the spectroscopic data, including a discussion of the coupling constants. In compound 2, suggest a probable stereochemical assignment for the methyl group marked with a

Answer

Qu 15. The 1,3 elimination of HCl from the imidoyl chloride isomers shown proceeds rapidly at 0*C to give the two compounds 3 and 4. On standing at room temperature, these rearrange to "X" or "Y", for which the following spectral data are obtained. X: dH 0.56 (3H, d, J 6.2 Hz), 2.40 (1H, dq, J 9.8, 6.2 Hz), 2.85 (1H, d, J 9.8 Hz), 8.51 (1H, s), 7.18-7.55 (9H, m); dC 5 (q), 15 (d), 33 (d), 54 (s), 155 (s) + aromatics. Y: dH 1.08 (3H, d, J 6.2 Hz), 0.49 (1H, dq, J 5.5, 6.2 Hz), 2.66 (1H, d, J 5.5 Hz), 8.16 (1H, s), 7.25-7.55 (9H, m); dC 28 (q), 14 (d), 32 (d), 58 (s), 153 (s) + aromatics. On refluxing in benzene, either "X" or "Y" interconvert via the presumed intermediacy of compound 5, which in turn slowly isomerises to 6, the final isolated product. Suggest structures for "X" and "Y" based on spectral and mechanistic evidence and propose likely mechanisms for their formation and subsequent reactions, paying particular attention to the stereochemistry of the species involved. (Hints: Try drawing alternative resonance forms of 3 and 4, and pay particular regard to the differences in the chemical shifts of X and Y. The multiplicities of the carbon nmr signals are those obtained with off-resonance decoupling).

Answer

Qu 16. The synthesis of the naturally occuring coumarin ester Gravelliferone is accomplished by heating the compound [1] in the presence of weak base. Two intermediates [2] and [3] are thought to be implicated in the mechanism. Suggest a possible structure for [2] and mechanisms for the overall transformation, indicating any steps that might involve the base.

Answer

Qu 17. 1-Nitropropene when added slowly to a solution of phenyl isocyanate and triethylamine (which together act as a dehydrating reagent) in the presence of norbornadiene forms a mixture of two isomeric compounds A and B. These both show three similar vinylic nmr peaks, but are distinguished by different couplings in the non-vinylic region. A: δ3.45 (J 8, 1.5 Hz), and 4.82 (J 8, 1.3 Hz) and B: δ3.87 (J 9.5, 4.2 Hz), and 5.29 (J 9.5, 4.3 Hz). Flash vacuum pyrolysis of A+B yields cyclopentadiene and a new compound C, the latter having the following 1H nmr spectrum: δ 5.61 (J 10.9, 0.9Hz), 5.90 (J 17.8, 0.9 Hz), 6.47 (J 1.7Hz), 6.8 (J 17.8, 10.9 Hz), 8.32 (J 1.7 Hz), which includes three vinylic and two aromatic resonances, and one surprisingly low ortho aromatic coupling. Suggest structures for A, B and C, mechanisms for their formation and an interpretation of the different couplings manifested for A and B (Hint: try using the MacroModel modelling program).

Answer

Qu 18. Random dot autostereograms are a way of representing three dimensional images. Does this compound contain any chiral centres?

Answer

Qu. 19. The transformation of [A] to [B] by heating has been extensively studied kinetically. The evidence seems to suggest that direct conversion does not occur. Synthesis of the triene [Z] suggests it is converted to [B] very rapidly. Mechanisms have been proposed which indicate that whilst direct conversion of [A] to [Z] is possible, it cannot be the exclusive pathway, since an intermediate [E] is detected during reaction. [E] cannot convert thermally to [Z] at the temperatures used, but would have to go via [Y]. It is also possible that [Y] too is formed directly from [A], but this is thought less likely on steric grounds.

Suggest possible structures for [E], [Y], [Z], mechanisms for all the possible conversion routes shown with arrows below, and explain the cause of the steric grounds referred to above.

Answer

Qu. 20. Reaction of two equivalents of the [1,3] dipolar species [S] with pyridine gives a 43% yield of the adduct [P]. The 1H NMR of [P] is δ 3.15 (dd, J 17, 6.8Hz), 4.00 (dd, J 17, 11.5), 6.20 (dd, J 11.5, 8.5), 6.42 (dd, J 11.5, 1.2), 6.45 (multiplet, J 11.5, 8.5, 6.8, 1.2), 6.8-8.4 (20H, aromatics). Three intermediates [M], [N and [O] are thought to be involved. Suggest possible structures for [N] and [P], together with mechanisms for their formation, assignment of the NMR data for [P] and any stereochemical conclusions derived from this data.

Answer

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 21. When compound 1 is treated with base and heated, it rearranges to give the products shown. The 13C isotope is distributed unequally between two products. Explain this result in mechanistic terms, and clearly indicate the type of reactions occurring and their nomenclature.

Answer

Qu. 22. Propose a mechanism for the following transformation.

Answer

Qu. 23. Shown below are stages in the total syntheses of two interesting molecules. Describe the type of reaction occuring at each stage, including details of nomenclature and the number of electrons involved. Suggest structures for the intermediates A, B and C, and propose mechanisms for each stage.

Answer

Qu. 24. The molecule below when heated gives rise to varying amounts of the products D-H. Propose mechanisms to account for the formation of each product. Some of these reactions will be pericyclic reactions, some (such as the aromatising loss of hydrogen) will include steps that are not. Indicate clearly which are the pericyclic steps.

Answer

Qu. 25. Xestoquinone is a marine natural product, part of the synthesis of which is shown below. A and B in the presence of a suitable oxidant, give racemic C (only one enantiomer shown). Mild heating gives an intermediate X, which has the 1H NMR spectrum shown below. Reflux at a higher temperature induces X to rearrange to a compound Z, a precursor to Xestoquinone. Suggest a structure for X compatible with the spectrum, and mechanisms for its formation and conversion. Pay particular regard to the stereochemical centres shown.

Optional for tutorials: Using a suitable molecular modelling technique (CAChe, Chem3D, MacroModel), try to identify whether Z is more or less stable than your proposed structure for X. Several other regio and stereo isomers for X and Z might suggest themselves from your proposed mechanisms. Are they higher or lower in energy?

Answer

Qu. 26. Treatment of di-isopropyl squarate ( K) with two mol equivalents of lithio cyclopentene in THF results in the intermediate L. This is presumed to rapidly rearrange via the intermediate M to the lithio-dianion N. Semi-quenching of this dianion to a lithio-monoanion results in isolation of the predominant final product O (along with the enantiomer), the relative stereochemistry being that shown, and the overall reaction being remarkable for the five contiguous stereochemical centres formed from the achiral precursors.

Given that L => M => N are pericyclic steps, and that N => O is not, deduce possible structures for M and N and mechanisms for their formation. Using what you know about these mechanisms, comment on the expected relative stereochemistry of any chiral centres in N, and speculate upon the relative stereochemistry of any further chiral centres formed in O.

Working back from the structure of M, deduce what the relative stereochemistry of the chiral centre shown with a wavy line in L might be. Speculate why this relative stereochemistry might be favoured in the reaction of K with lithiocyclopentene

Answer

Qu. 27. A key step in the synthesis of the natural product Lycopodine is shown below. Suggest a mechanism for this reaction, indicate clearly whether each step in the mechanism is a pericyclic or non-pericyclic process, and classify each pericyclic process according to its type.

Answer

Qu. 28. In the sequence shown below, treatment of the reactant with sodium thiophenoxide (a base and also a thiophile) produces two transient isomers X and Y prior to the final product Z. The product Z has the following spectral characteristics. nmax 3610 cm -1, 1H nmr d 2.0 (1H, broad s), 2.26 (3H, s), 2.8 (1H, m, J 13.6, 7.8Hz), 2.9 (1H, J 13.6, 5.8),4.40 (1H, J 7.8, 7.0, 5.8 Hz), 5.5 (1H, J 15.6, 7.0), 6.33 (1H, J 15.6), 7.4-7.6 (5H, m). Suggest a structure for Z, and a mechanism for its formation. Indicate clearly whether each step in the mechanism is a pericyclic or non-pericyclic process, and classify each pericyclic process according to its type. Pay particular attention to the stereochemistry of Z

Answer

Qu. 29. The 1H NMR spectrum of the compound shown below has some very peculiar properties. At -50C, four peaks are observed at d 5.73 and 6.25 (assigned to the olefinic protons) and at 6.95 and 7.04 (assigned to the aromatic protons). As the temperature is increased to about 20C, the two peaks due to the olefinic protons coalesce to a single peak, as do the two aromatic peaks. Further heating to 120C results in each now single olefinic and aromatic peak further coalescing to a single peak, as do the two singlets due to the Bu t groups. On cooling, this behaviour is entirely reversible. Suggest pericyclic mechanisms to explain the behaviour observed at both 20C and 120C.

Answer

Qu. 30. Part of the synthesis of the natural product Histrionicotoxin involves the following transformation, involving intermediate A and product B. A undergoes further thermal conversion to give a precursor of Histrionicotoxin C. Suggest structures for A and B, and mechanisms for the reactions involved. Comment on any possible regio-isomers that might also be possible for C and indicate the expected stereochemistry of the bond to the cyano group (shown with a wiggly line in the diagram below).

Answer

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 31. The dicyclopentacyclo-octenyl ring system is common to many natural products. A particularly efficient synthesis of one such system is shown in part below. The first stage involves photolysis of the two reactants shown (R=Me) to produce an intermediate W as a single regio- and stereoisomer. If R=H, a mixture of two regioisomers is produced. Subsequent thermolysis of W (R=Me) produces the final product Z, accompanied by an unexpected change in the stereochemistry at the C-8 carbon. This last observation implicates the intermediacy of X and Y. Discuss the following aspects of these reactions.

1. Classify the mechanism of the reaction resulting in the formation of compound W. Pay particular attention to the stereochemistry of this product. (8 marks)

2. Suggest a structure for the additional regioisomer formed when R=H and suggest a reason why this regioisomer is not formed when R=Me. (8 marks)

3. What other stereoisomers possible for W are consistent with the mechanism you propose in 1 above? Suggest a reason why they are not formed (Hint: you might have to build models to answer this part, ideally using a modelling program). Are there yet more stereoisomers possible which would be inconsistent with the mechanism you propose? (9 marks)

4. Classify the mechanism of the reaction resulting in the formation of the presumed intermediate X, paying particular attention to explaining its stereochemistry. (9 marks)

5. On the basis of the mechanism you give in 4, can you suggest an isomer of X, which might also be possible? (Hint: consider the stereochemistry of the double bonds). (8 marks)

6. Suggest a pericyclic mechanism which would involve the formation of another intermediate Y which might explain the inversion of stereochemistry at C-8, indicating your proposed structure of Y (Hint: rotation about single bonds in intermediate Y might be possible). (9 marks)

7. What would be the consequence of applying the mechanism proposed for the formation of Y to the stereoisomer of X implied in 5? (9 marks)

Answer

Qu 32. The reaction sequences 1 - 4 shown below each involve pericyclic steps. Suggest a possible mechanism for each sequence, together with structures (discuss any stereo or regio-chemical features) for the various unidentified intermediates labelled [A] through to [J], indicate what type of pericyclic reaction, if any, is involved (including appropriate nomenclature), which electron counting rule (4n+2 or 4n) applies and whether the reaction will involve a Huckel or a Mobius transition state.

1.

(10 marks)

2.

(10 marks)

3.

(Hint: [D] is monocyclic and [E] is bicyclic).

(12 marks)

4.

The last step from [J] is assumed to take place in the scrupulous absence of any traces of acid or base catalyst. What mechanism might prevail for this step if such catalysts were indeed present? (18 marks)

Answer

Qu 33. As part of a strategy for the synthesis of natural products such as the marine alkaloid hyellazole, the following annelation procedure was developed. Compound U was photolysed, resulting in loss of nitrogen and rearrangement to give a reactive intermediate V. This was treated with the alkyne shown under thermal conditions to give another transient intermediate W, which upon standing thermally rearranged via two more intermediates to the final product Z, the last being in equilibrium with Y. Propose structures for V, X and Y (12 marks) and mechanisms for their formation (13 marks). Include in your answer details of any pericyclic processes involved, including nomenclature and selection rules.

Answer

Qu 34. An elegant synthesis of the diterpenoid core of natural products such as tetrodecamycin or the antimalarial drug arteannuin is based on the following reaction. The starting material A is heated (actually as the oxy-anion to accelerate the reaction) to produce a transient intermediate B, which soon isomerises to C (hint: think keto-enol tautomerism for this last reaction). On further heating, C gives mostly isomer D, with traces of E. D in turn rearranges to a transient intermediate F, which again rapidly equilibrates with G (hint: more carbonyl chemistry). Compared with the reactant, G has two new chiral centres (marked with a *), which are formed with high stereospecificity and a third that is not (marked with a wavy bond). The trace isomer E instead gives the alternative diasteroisomer H. Identify the intermediates B, C and F (9 marks) and the pericyclic mechanisms involved in this sequence, including any nomenclature and selection rules you can readily assign (11 marks). Try to propose a model (5 marks) for showing how C can give both D and E (you do not have to explain why D predominates over E) and why D gives the stereochemistry shown in G, whilst E gives H (hint: think chair).

Answer

Qu 35. The following sequence is part of a biomimetic synthesis of propionate derived natural products. The tetraene ester is heated to give the tricyclic core B of the natural system, via a presumed intermediate A. Propose a structure for A (10 marks), mechanisms leading to it and B, including nomenclature (10 marks) and using your knowledge of the predicted stereochemistry of your mechanistic steps, predict the stereochemistry of the centre to which the ester group E is attached (5 marks).

Answer

Qu 36. The biomimetic synthesis of a potent microtubule-stabilizing agent involves the use of an acyclic precursor C to create the complex pentacyclic chemotherapeutic molecule F, forming seven new stereogenic centres in a fully diastereocontrolled fashion. The step C to D is a conventional macrocyclisation, whilst E to F is a simple lactonisation. Your task is the following;

1. to propose a mechanism for the thermal transformation D to E (it may involve more than one step!). Include nomenclature of any mechanistic steps (13 marks),

2. to deduce stereochemistry for the two stereogenic centres shown with a wavy line (2 marks).

3. to identify the five other new stereogenic centres in E. (5 marks),

4. if their stereochemistry is indicated in the diagram, to show it is consistent with the mechanism(s) you propose, giving your reasons (3 marks),

5. if their stereochemistry is NOT indicated in the diagram above, to complete it (2 marks).

Answer

Qu 37. The following sequence of reactions starting from compound A (the four bonds marked with a b are in fact benzo derivatives of the alkene, not shown below to retain clarity in the diagram) and B was recently reported as the culmination of a "holy grail" target in chemistry. Reaction via intermediates C, D led to an isolable mixture of two isomers E (each showing the presence of six alkene C-H 1H resonances, as well as aromatic resonances resulting from the benzo groups), one of which was claimed to have a structure with an C2 axis of symmetry and the other a plane of symmetry. Further gentle irradiation led to an equilibrium mixture of five isomers of the [16] annulene F. One of these, after separation by HPLC, proved to be the long sought molecule (and also exhibited a C2 axis of symmetry). Suggest mechanisms for the various transformations, possible structures for the intermediates corresponding to C, E and (only one of) F, and include discussion of why a [16] annulene with a two-fold axis of symmetry might arouse such interest. (Hint: the stereochemistry of the intermediates may not always be unambiguous or necessarily follow selection rules, a point which you might wish to discuss).

Answer

THE END

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 31

1. The π2s + π2s cycloaddition is a 4n electron photochemical allowed process proceeding with suprafacial addition across both alkene components (M. L. Randall, P. C. K. Lo, P. J. Bonitatebus and M. L. Snapper, J. Am. Chem. Soc., 1999, 121, 4534).

2. The alternate regioisomer

of W is not formed when R=Me (or larger) due to steric hindrance between the two methyl groups (see molecular models).

3. Three other so-called endo/exo stereoisomers of W are all consistent with the π2s + π2s cycloaddition. Molecular modelling can be used to establish the relative energies of all four isomers. The one actually formed is found to be lower in free energy than the other three, largely a result of minimisation of the steric repulsions between the R group and other atoms. Other stereoisomers could result from π2s + π2a addition across the two alkenes to give a trans ring geometry, but such stereochemistry would not be consistent with the rules for a 4n electron photochemically mediated cycloaddtion.

W (formed, 0.0) (doi: 10042/27408)

W (regio isomer, +2.2) (doi: 10042/27407)

W (stereoisomer, +10.4) (doi: 10042/27409)

W (stereoisomer, +15.6) (doi: 10042/27410)

W (stereoisomer,+5.3) (doi: 10042/27411)

4. Thermolysis requires a π2s + π2a retro- cycloaddition (4n electrons, Mobius transition state with an antarafacial component). The antarafacial component can be located on either of the forming two alkene bonds. For isomer X, this produces the cis alkene shown, twisting the original trans relationship of the two hydrogens on these two carbons by 180 degrees.

X (+0.8) (doi: 10042/27412)

Y (+7.1) (doi: 10042/27413)

Y carbonyl atrop (+12.0) (doi: 10042/27421)

Y (rotamer,-+7.3) (doi: 10042/27415)

Z (-13.7) (doi: 10042/27417)

Isomeric X (+0.3) 10042/27416

Isomeric Y (+12.8)

Isomeric Y (rotamer, +14.1)

Isomeric Z (-14.3) (doi: 10042/27414)

5. Locating the antarafacial component on the other possible forming alkene results in the following isomer of X:

6. Compound X has the characteristic 3-single/two-double bond pattern associated with the [3,3] sigmatropic Cope rearrangement. This is actually possible in two directions, but we concentrate on the one that creates an sp^2 centre at C-8, the atom at which inversion of configuration is observed to occur. This produces a flexible 9-membered ring, which can flip the trans alkene bond by atropisomerism (rotation) about the adjacent single bonds, to produce a conformer with the C-8 hydrogen pointing up. Reverting the [3,3] sigmatropic reaction using this conformation will now reform the 5-8-5 ring system but with the correct stereochemistry at C-8.

7. Repeating the sequence of events on the isomer of X produces the following compounds, i.e. bond rotation about the trans alkene and [3,3] Cope reclosure now inverts the configuration at the C-7 carbon. Molecular modelling indicates this pathway is only about 20 kJ/mol higher than the observed one, suggesting this might be a minor (unobserved) product of this reaction.

Qu 32

1. 4n+2, Huckel 2+4 cycloaddition to give [A], followed by 4n+2 Huckel cycloelimination. Two possible regio-isomers are possible for [A] (bonus mark if you spotted this).

2. Electrocyclic 4n Mobius ring opening (as per lectures) followed by rotation around the single bond indicated and electrocyclic ring closure to distribute the deuterium atoms as shown.

3. Two successive electrocyclic reactions, the first 4n via Mobius to give the trans dimethyl stereochemistry, the second 4n+2 via Huckel to give the cis-ring fused system. Then 4n+2 Huckel cycloaddition (two possible stereoisomers, but one is more sterically hindered than the other) followed by cycloelimination of a cyclobutene, which then opens in a 4n Mobius electrocyclic reaction to give the trans hexadiene. This problem becomes more tractable if the starting material is redrawn into a cyclisable form by rotating about formally single bonds, hence the hint!

5. A Mobius 4n 2+2 cycloaddition typical of that found for many ketenes gives a cyclobutene, which opens via an electrocyclic 4n Mobius to a diene. A second 4n+2 electrocyclisation is followed by a [1,7] sigmatropic shift of the H atom via a Mobius (antarafacial) migration. If traces of acid or base are present, then a normal catalysed keto-enol tautomerism will occur instead.

Qu 33

Photolysis of U results in a carbene, which undergoes a 4n [1,2] sigmatropic shift (the Wolff rearrangement) to give the ketene V. This undergoes a p2s + p2a cycloaddition (Mobius transition state) with the alkyne to give the cyclobutenone W, which in turn opens by an electrocyclic 4n reaction (Mobius transition state) to give either X (conrotation in one direction) or XÕ (conrotation in the other direction). Only X is capable of further 4n+2 electrocyclisation (Huckel transition state) to give Y, which then tautomerises to give the phenol Z. For more details, see R. L. Danheiser et al, J. Am. Chem. Soc., 1990, 112, 3093.

Qu 34

A to B is a typical [3,3] sigmatropic rearrangement (two double bonds separated by three s bonds) and is a 4n+2 thermal process proceeding via a Huckel transition state with suprafacial stereochemistry. The enol so formed rapidly tautomerises to the ketone C, which then undergoes an ene reaction (two s bonds formed, one broken) to form D, also a 4n+2 Huckel reaction. Either one of the two hydrogen atoms on the prochiral CH2 group (differentiated as Pro-R and Pro-S) can be transferred resulting in E or Z double bond isomers, via a transition state the more stable of which leads to D and the less stable to E. D/E again have the pattern of two double bonds separated by three sigma bonds, which allows another [3,3] sigmatropic reaction to occur, via a chair 4n+2 Huckel transition state in which the new C-C bond is formed suprafacially to create two new chiral centres in F/H (see models). This rapidly and non-stereospecifically cyclises to the final product G. The other double bond isomer E which [3,3] cyclises via another chair transition state to H does so with the opposite configuration at the benzylic carbon (see the 3D models to really convince yourself this is true). For more details, see L. Barriault and I. Denissova, Organic. Letters, 2002, 4(8), 1371-1374. 3D models for these transition states can be viewed at http://www.ch.ic.ac.uk/local/organic/tutorial/rzepa6/.

Qu 35

See here.

Qu 36

See here.

Qu 37

See here.

THE END

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 21

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Qu 22

Qu 23

Qu 24

Various cycloaddition or electrocyclisation reactions are possible, followed by either acid/base catalysed [1,3] H shifts (these are not possible as pericyclic reactions) or just possibly [1,7] H sigmatropic shifts. The original literature citation is Tetrahedron, 1992, 48, 7425.

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Qu 25

The reduction in 1H NMR vinyl protons ( d 5.0 - 5.8) from 8 in the reactant C to 4 in the intermediate X suggests a p2s+p4s Diels-Alder type cycloaddition reaction involving a diene and an alkene component. The strongly non-equivalent methylene protons adjacent to O ( d 3.85, 4.15) implies the adjacent carbon is chiral. If the diene component is taken as part of the 6-membered ring, then either of the double bonds in the butadiene sidechain can act as the dienophile, each addition having two different regiochemistries. Of these four possible products, only two have precisely 4 vinylic protons and an oxy-methylene next to a chiral centre, i.e. X and one isomer.

The other possibility is that the sidechain acts as the diene and either of the double bonds in the 6-ring acts as the dieneophile. One addition mode leads directly to Z itself (we assume that Z and X are different!). The other addition mode would give rise to species with only 3 vinylic protons,

The compound shown as X can undergo a simple [3,3] sigmatropic shift to give Z directly. The other isomer compatible with the NMR data cannot be converted to Z. The stereochemistries of the Diels-Alder additions all result from suprafacial addition across both the diene and the alkene, as required by the selection rules, whilst a suprafacial migration in the [3,3] rearrangement gives the stereochemistry shown for Z.

Molecular Modelling. Use of a modelling method such as PM3 (semi-empirical molecular orbital) allows relative energies for all the putative species involved to be calculated. That for compound C is calculated as -49.3 (kcal/mol), with the corresponding values for each possible intermediate and product being shown against the structure above. As can be seen, the most negative (most stable) corresponds to the intermediate X, whilst the most stable product is also the one actually formed. These relative energies are associated with the minimisation of bond angle and torsion strains in the cyclic systems. Models for all these species can be inspected here

Literature Reference : R. Carlini, K. Higgs, C. Older, S. Randhawa, and R. Rodrigo , J. Org. Chem ., 1997, 62, 2330.

Qu 26

L might be expected to form with the two oxylithium centres anti, to minimise charge repulsion and to accommodate the lithium counterion solvated with THF. Electrocyclic ring opening (accelerated by the oxyanion characteristics) proceeds with conrotation (4n electrons, Mobius transition state) to give M, again with the two oxylithium centres presumed on the "outside" to minimise charge repulsion (torquoselectivity). Electrocyclic ring closure conrotation (4n electrons, Mobius transition state) proceeds with an antarafacial component to give predominantly trans stereochemistry at the newly formed C-C bond. Protonation of one enol centre gives the more stable cis 5-ring fusion. The final product is formed by a simple aldol condensation from N, again in a manner which gives a cis ring fusion. Molecular modelling reveals this stereoisomer to be significantly more stable than the trans fused form. Interestingly, the mono-anion of N can exist in two conformations, with the carbonyl group oriented either syn or anti to the adjacent fused 5-ring. The syn ("up") form is the one that leads to the final observed stereochemistry of the resulting alcohol, although it is actually slightly less stable than the anti isomer. This suggests that aldol formation is a reversible process driven by the thermodynamic stability of the final product.

Literature Reference: L. A. Paquette and T. M. Morwich, J. Am. Chem. Soc ., 1997, 119, 1230.

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu 11. a)

Y. Himeda, K. Hiratani, M. Hatanaka and I. Ueda, J. Chem. Soc., Chem. Commun, 1992, 1684. b)

T. Mosandl, C. O. Kappe, R. Flammang and C. Wentrup, J. Chem. Soc., Chem. Commun, 1992, 1571.

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Qu 12,

C. O. Kappe, G. Kollenz and C. Wentrup, J. Chem. Soc., Chem. Commun, 1992, 485.

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Qu 13.

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Qu 14. See K. Harano, M. Eto, K. Ono, K. Misaka and T. Hisano, J. Chem. Soc., Perkin Trans 1, 1993, 299 for further details.

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Qu 15. Species 3 and 4 appear to react as carbenes! The two isomers X and Y are distinguished by the different chemical shift values of the Me and H groups induced by the adjacent aromatic ring (anisotropy). The observation that both X and Y can be isolated eliminates the possibility that 5 is formed directly from 3 or 4 by a 4n electron electrocyclisation (assuming the inversion barrier in 5 is small!). Another possibility of 3 or 4 acting as 1,3 dipoles and adding directly to the alkene to give X or Y is eliminated by spectral evidence and the necessity of the resulting cyclobutene having to ring open with disrotation (Huckel ts) to give 5, a process not favoured by the selection rules. See K R Motion, I. R. Robertson, J. T. Sharp and M. D. Walkinshaw, J. Chem,. Soc., Perkin Trans 1, 1992, 1709 for further details.

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Qu 16N. Cairns, L. M. Harwood and D. P. Astles, J. Chem. Soc., Perkin Trans 1, 1994, 3101, propose a so called "tandem" series of [3,3] sigmatropic rearrangements, also known as Claisen rearrangements, for the synthesis of a series of natural coumarins.

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Qu 17 P. W. Ambler, R. M. Paton and J. M. Trout, J. Chem. Soc., Chem. Commun., 1994, 2661, report the use of norbornadiene as an acetylene equivalent. The two adducts A and B are exo and endo isomers, which are distinguished by different 3J couplings, as predicted by the Karplus relationship. Molecular models show that the vicinal angle in the exo isomer (~ 75*) is close to the minimum in the Karplus function, whereas the endo isomer (~ 40*) should exhibit larger couplings. The angle of ~ 0* for the vicinal bridgehead protons leads to a medium sized coupling. The ortho coupling in the isoxazole product is surprisingly small, although it is in fact typical for such systems.

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Qu 18 Random dot autostereograms are restricted to representing images in a series of planes. It is not possible to represent continuously varying depth. The structure here is Gravelliferone (really!).

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Qu 19

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Qu 20

The abnormally high chemical shift of the 5-H proton at 6.45 ppm originates in part from the adjacency to N (which defines the chemospecificity) and in part from the 3D structure of the molecule, which places it in the (deshielding) plane of the other heterocyclic ring. To rotate this model, click here. Back to Problems

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Practice Problems in Pericyclic Reactions.

The following are a set of practice problems in Pericyclic Mechanisms, prepared by Henry Rzepa for the for a second year course in Pericyclic Reactions at the Department of Chemistry, Imperial College. Each of these problems is intended to take between 1-3 hours to solve. They are NOT typical of examination questions! Please note also that the compound numbers are not consecutive between questions.

Qu. 1. Cycloelimination of CO2 from 1 gives the transient species 2 (4n+2 electrons, Huckel transition state, thermally allowed). This is followed by either a [1,5] sigmatropic hydrogen shift (4n+2 electrons, Huckel t.s., thermal) to give 4, subsequently hydrolysed to 5, or by a p2s + p4s intramolecular cycloaddition to give the other product 3.

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Qu. 2. Formed by cycloelimination of CO2 from A, via a 4n+2 electron Huckel transition state (thermally allowed). B then undergoes a 4n+2 electrocyclisation (Huckel t.s.) utilising either of the two single (alkene like) bonds of the three membered ring to form C or D. These can then undergo a 4n cycloelimination of PhCN (thermal, therefore must proceed via a Mobius transition state with one antrarafacial component) to give E.

E can undergo an electrocyclisation (4n+2, Huckel, thermal) to give F, which can aromatise by TWO consecutive [1,5] sigmatropic hydrogen shifts (4n+2, Huckel, thermal) to give the final indole product G.

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Qu. 3. a) This is an example of the "Domino Diels Alder Reaction", L. A. Paquette et al, J. Am. Chem. Soc., 1978, 100, 5845.

b) J. Chem. Soc., Chem. Commun, 1988, 777.

Qu. 4. The preparation of "felicene", A. Gilbert and R. Walsh, J. Am. Chem. Soc., 1976, 98, 1606.

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Qu.5. a) The reaction is a [1,3] sigmatropic migration occuring thermally with 4n (n=1) electrons. Hence one antarafacial component must be present, and inversion at the starred atom occurs, resulting in the observed stereochemistry.

b) The absence of both the cyclopropyl and carbonyl groups implies cleavage of the 3-ring, most probably via either [1,3] or [3,5] sigmatropic migration. The presence of only one non-vinylic proton (at d3.76) in the nmr rules against the [1,3] migration and in favour of [3,5] thermal migration (4n electrons and hence one antarafacial component). Models show that this can be easily accomodated on the 3-atom component if bond a forms to the bottomface of the carbonyl p system and bond b breaks from the top face of the C(Ph)-C=O system. Both bonds form/cleave from the top face of the 5-atom component as shown below. This results in the cis ring junction stereochemistry.

See P J Battye, D W Jones and H P Tucker, J. Chem. Soc., Chem. Commun.,1988, 495.

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Qu. 6. DMAD is a reagent that reacts readily with dienes. Two independent 4n+2 electron thermal electrocyclic reactions convert ditropyl into two separate diene units, followed by 4n+2 thermal cycloaddition of the DMAD to give [B]. Four different stereoisomers are possible, but the two unsymmetrical forms are ruled out from the nmr evidence. Distinction between the two symmetrical forms could have been made on the basis of the coupling constant (3Hz), which is known from other examples to be ca 4Hz for the isomer shown and ca 9Hz for the alternative isomer. A double 4n+2 cycloelimination gives rise directly to [C] and [D]. [C] is an isomer of benzene, to which it rearranges via probably homolysis of the cyclopropyl bond.

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Qu 7. a) Comparison between reactant and product suggests they differ only in the position of one hydrogen (by 5 carbon atoms) and a C-C bond;

See valso DOI 10.1016/S0040-4020(01)87607-9.

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Qu. 8. The reversible nmr behaviour suggests an equilibrium between two species, involving the interconversion between an alkene (d 6.3-4.8) and an alkane (d3.3-1.4). At high temperatures, the chemical shift of two hydrogen is averaged to the mean position (d3.82). Hydrogenation 'traps' out the 'alkane', whilst heating 'traps' out the alkene by further (Cope) reaction.

A number of cis/trans isomers for the 10-ring cycloalkene are possible, of which models suggest one in which the new double bonds are formed trans is most likely (see below).The trans form can exist in two different conformations, for both of which the s bond cleaving and the s bond forming are suprafacial on each C3 fragment of the [3,3] sigmatropic rearrangement. The conformation resulting in trans stereochemistry for 6 must be the more stable;

When this species cyclises to 7, this conformation sets the bond up to form from the bottom face of one end of the octatetraene component, and the top face of the other end, to form the trans stereochemistry in the 4-ring. The other possible conformation appears less likely to result in the required stereochemistry;

The conformation where the two double bonds are formed cis looks like this;

A quantitative estimate of the relative stability of these three forms can be obtained by "molecular mechanics" modelling (ie using the MODEL program). Their energies are 114, 139 and 135 kJ mol-1 respectively, which conforms that the stereochemistries of the products are controlled by the conformational stability of the intermediate 10-ring.

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Qu. 9.

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Qu. 10.

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Bonus Examples.

The final set of examples show how one can push the rules to their limits; these all constitute quantum predictions and remain to be discovered experimentally! This section is not examinable!

1. Two (hypothetical) examples of cycloaddition with an even number of antarafacial components. The first is a π4[a] + π6[a] cycloaddition, again following a 4n+2 rule of aromaticity.

This is a π2[a] + π2[a] + π2[a] + π2[a] photochemical (4n, even antarafacial = hν) addition and was contrived by Woodward and Hoffmann themselves to illustrate the point.

2. A [1,5] migration of a methyl group can either go suprafacially with retention of configuration at the methyl (preserving a plane of symmetry) or antarafacially with inversion of configuration at the methyl (preserving an axis of symmetry). This last reaction corresponds to two antarafacial components. In such a small (six-membered) ring, the latter is calculated to be 23.4 kcal/mol (98 kJ/mol) higher in free energy than the suprafacial/retention

But increasing the ring size to ten, as in a [1,9] methyl shift is predicted to result in a double-Möbius [1,9] antara/inversion mode being 15.2 kcal/mol lower in free energy than the more conventional Hückel [1,9] supra/retention route! In reality, lower energy [1,5] shifts are likely to compete with both the [1,9] shifts.

3. A ten-electron [5,5] sigmatropic rearrangement with two antarafacial components (and following the 4n+2 rule) might be possible. Note the "figure-8, double S" shape.

4. An example with four antarafacial components, two for methyl transfer with inversion, and two for antarafacial transfers across a chain. Its even possible to formulate reactions with six antarafacial components!.

The End (for real)

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The Frontier Orbital approach

The Frontier orbital approach is getting more complicated, and this is the only example considered in detail. The HOMO of one molecule and the LUMO of the other must overlap in phase. In this example of a Diels-Alder cycloaddition reaction, there are therefore two combinations that must be considered; the HOMO of the "diene" with the LUMO of the "ene", and the LUMO of "diene" with the HOMO of "ene". For this example, both give the same result, but this need not always be the case.

An extension of this frontier orbital approach is to state that the two LARGEST orbital nodes will overlap with one another, and the two SMALLEST will also match up. The size of the orbitals must be obtained from detailed quantum mechanical calculations. Such considerations can explain much pericyclic regiochemistry, as for example in the dimerisation of acrolein or butenal:

One final extension of this approach, to consider not just the primary HOMO/LUMO overlap but other overlaps as well (so called secondary orbital overlaps) is required to explain why the Diels Alder reaction shows an endo rather than an exo preference. This however is beyond the scope of the present lectures.

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Tabular Pericyclic Reaction Selection Rules

Condition

+ Electron count

+ Stereochemistry ⇒

Topology

≡ Lk

1: Heat (Δ)

4n+2

Suprafacial‡

Hückel

0†

2: Light (hν)

4n

Suprafacial‡

Hückel

0†

3: Heat (Δ)

4n

Odd antarafacial

Möbius

Odd

4: Light (hν)

4n+2

Odd antarafacial

Möbius

Odd

Diagrammatic Pericyclic Reaction Selection Rules

Frost, Musulin and Zimmermann diagram (1965)

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2.3. Lemniscular or Double-twist Möbius Rings

In 2005, the Möbius approach was extended by Rzepa to rings created by imparting two half-twists to a cyclic array of 2p-AOs. They are equivalent to molecules with two antarafacial components, but components which do not cancel each other. They retain the C_2 axis axis of symmetry (in fact they can have three such axes). Such systems, like the single half-twist topology, are also chiral (disymmetric). The molecular orbitals (and the electron density) take the form of 2[1][2] torus links having linking numbers of two, and these often exhibit figure-8 (lemniscular) shapes (See DOI: 10.1039/b510508k and 10.1021/ol0518333).

It was recently recognized that this figure-eight is stabilized by a topological property known as writhe (or in molecular biology, supercoiling), which makes such geometries far more likely and accessible than they otherwise would be (DOI: 10.1021/ja710438j). Systems with up to six half twists have now been identified (DOI: 10.1021/ic800987f) and there is also a fascinating link to biological molecules known as cyclic or supercoiled DNA (DOI: 10.1016/j.cub.2006.02.029). Another bit of coiled helical fun!

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Instructions for viewing NBO Orbitals

These instructions are based on using the following programs:

- Gaussian09

- Cubegen from Gaussian 09

- Gaussview 5

- Jmol

The procedure is as follows:

1. Use Gaussian keywords of the type:
rwb97xd/6-311g(d,p) pop(nbo,SaveNBOs)

(this presumes the geometry has already been properly optimised)

2. Obtain the .fchk file (this is automatically available if the job has been run via the uportal)

3. Using Gaussview, double click the .fchk file and invoke edit/MOs

4. Visually identify the index numbers of the filled orbital/empty orbital combination you want to illustrate. Let us say that they are orbital 35 and orbital 41 for example.

5. In Gaussview go to Results/Surfaces-contours, select an orbital and from cube actions, save it to disk.

6. Or, instead of the previous step, locate a computer with the cubegen utility installed on it, and type the following command:

./cubegen 0 MO=41 dichloropyran.fchk dcp-41.cub 0

./cubegen 0 MO=35 dichloropyran.fchk dcp-35.cub 0

where dichloropyran.fchk is the original name of the .fchk file.

7. The cube files so generated (i.e. dcp-41.cub) are likely quite large. One can reduce the size of this vastly by processing it using Jmol. Run a (partially illustrated) .html file containing the following lines, in a directory also containing the Jmol signed applet:

<body>

<script type="text/javascript">

//<![CDATA[

jmolInitialize(".","JmolAppletSigned.jar")

//]]>

</script>

<script type="text/javascript">

//<![CDATA[

jmolApplet(800,'isosurface ch2 cutoff +0.02 color red sign "dcp-35.cub";color isosurface translucent;color background white;write isosurface @{"/Users/rzepa/documents/conformational-analysis/conf/dcp-35.jvxl"};')

//]]>

</script>

8. This generates a .jvxl file, which is tiny in comparison to the original cube file. Call this file from a (partial) Web page as follows:

<body>

<script type="text/javascript">

//<![CDATA[

jmolInitialize(".","JmolAppletSigned0.jar")

//]]>

</script>

<script type="text/javascript">

//<![CDATA[

jmolSetAppletColor("yellow");

jmolApplet([250,380],'load "dcp-35.jvxl";isosurface "" translucent;set fontscaling TRUE; font label 18;select atomno=11;color black;label %A O Lp orbital;','cs')

//]]>

</script>

Table of Contents

Home

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Relevance

Theory

Alkanes

Sub-alk

σ-π Conjugations

Cycloalkanes

Hetrings

Atrop

Prob

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molecule/transition state models

surfaces

Firefox

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diamond

Derek Barton

10.1021/ja01281a014

Natural bond orbitals, or NBOs

Unnamed

Unnamed

staggered/anti-periplanar conformation

Gauche conformation

eclipsed/syn-periplanar transition state

eclipsed/anti-clinal transition state

H...H

two σC-H/σ*C-F interactions, E(2) = 4.9

app conformation

Unnamed

Unnamed

Unnamed

optimal for a co-linear angle

Unnamed

Nos 2 and 3 in the previous lecture

(previous lecture)

Unnamed

Unnamed

H...H distance of this pair of hydrogens

eclipsed distance

eclipsed orientation

"outward leaning" C-H bonding orbitals

illustrated below

Unnamed

Unnamed

s-cis form

πLp/π*C-O 90.5

ν 105 cm-1

puckering process

by X-ray analysis