The aromaticity of Pericyclic reaction transition states

Henry S. Rzepa

Department of Chemistry, Imperial College London, South Kensington Campus,

Exhibition Road, London, SW7 2AY, UK

Abstract

An approach is presented which starts from two fundamental concepts in organic chemistry, chirality and
aromaticity, and combines them into a simple rule for stating selection rules for pericyclic reactions in terms of
achiral Hckel-aromatic and chiral Mbius-aromatic transition states. This is illustrated using an example which
leads to apparent contradictions if treated using more conventional selection rules, but is readily understood in terms
of the aromatic transition state model.

Background

The electronic theory of organic chemistry underpins one of the most interesting, but subtle, concepts currently
taught in the subject, that of the "stereoelectronic control" of reactions. For a particular mechanistic type known as
the pericyclic reaction, other concepts fundamental to organic chemistry such as stereochemistry, chirality,
aromaticity and quantum mechanics are interwoven. The impact of this fusion of ideas on organic chemistry has
been recognized with the award of a Nobel prize in 1981 to one the original architects, Roald Hoffmann (the other,
Robert Woodward, had died in 1979 and was ineligible to receive the prize posthumously). In this article, these
diverse concepts are brought together via an illustration of transition states for one specific pericyclic reaction which
played a key role in the first experimental synthesis of a new type of molecule, a Mbius annulene.

The discoverer of the electron itself, J. J. Thomson, was amongst the first to also develop models using the electron
to account for chemical bonding. In 1921, just before the dawn of quantum mechanics, he published 1 an exploration
of the bonding for the archetypal aromatic molecule benzene. In his scheme, each C-C region in this species was
bonded using three electrons (Scheme 1a). Reading his description, it is evident that the electron was still very much
regarded as a point particle, and that there was yet hardly a glimmer of recognition that the group of three electrons
might have differing spatial (3D) characteristics. The advent of quantum mechanics and the formulation of the
Schroedinger wave equation brought with it an understanding of the spatial and energetic properties of electrons,
more formally described by wavefunctions. This allowed a segregation of two of Thomson's three electrons in each
C-C region of benzene into a low energy set, which form what is now called a C-C bond, and the third electron
as contributing to a spatially distinct band of six rather higher energy electrons not directly associated with any
single C-C bond but with the aromatic ring itself, and which became widely known as the aromatic sextet (Scheme
1b).2

Scheme 1. (a) Thomson's three electron bonds in benzene and (b) the segregation of these 18 electrons into six pairs
of two electron C-C bonds and a aromatic sextet following Hckel.
The first person to formalize this separation was Erich Hckel in 1930. 3 He used the new theory of quantum
mechanics to derive a principle of / separability, which he used to explain the restricted rotation in alkenes.
Hckel in 1931 extended this concept to benzene itself, predicting particular stability for a cyclic arrangement of six
electrons in wavefunctions (Molecular Orbitals) formed by overlapping carbon-centered 2p atomic orbitals into a
planar ring. The concept of atomic orbitals themselves had previously been derived by solving the quantum
mechanical Schroedinger wave equation for a hydrogen atom. It took little while longer for organic chemists to
properly generalize and understand Hckel theory as a useful, albeit approximate theoretical basis for the wider
concept of aromaticity. The emergent Hckel rule (first succinctly coined not by Hckel himself but by William
Doering as late as 1951 3), is conventionally applied to planar molecules containing cyclically conjugated electrons
(referred to below as having Hckel topology) and is now enumerated as the following;

1. 4n+2 (where n is an integer) electrons, thermally (closed shell with all molecular orbitals doubly
occupied) aromatic and stable
2. 4n electrons, photochemically (open shell, with two molecular orbitals each occupied by a single
electron) aromatic and stable

3. 4n electrons, thermally anti-aromatic and less stable

4. 4n+2 electrons, photochemically anti-aromatic and less stable.

Rules 2 and 4 were added in the 1960s, as the quantum mechanical understanding of photochemically excited states
(open shell systems with two molecular orbitals each singly occupied) developed. These nowadays are regarded as a
much more approximate heuristics than the thermal rules 1 and 3.

A particularly characteristic feature of what might be called "classical" aromatic chemistry is the planarity (two-
dimensionality) of the ring. When the representation of a planar molecule is reflected in a mirror, the three
dimensional arrangement of atoms can be exactly superimposed on the original unreflected set; such molecules are
said to be achiral. A small class of aromatic molecules are forced to be non-planar for steric reasons. A good
example are the helicenes, which adopt a helical arrangement of the rings (Figure 1). When reflected in a mirror
plane, such a helicene cannot be superimposed upon the original and the system is said to exist as a pair of chiral or
disymmetric enantiomers. Of course, aromatic molecules can support chiral groups as substituents on the rings, but
we exclude this class in our argument here, since we are concerned only with the nature of the aromatic structures
themselves.

Figure 1. A heptahelicene and its non-superimposable mirror image.

Hckel and Mbius Aromatics

Thus these two great concepts of organic chemistry, aromaticity and chirality, remained mostly exclusive. Edgar
Heilbronner in 19644 and Howard Zimmerman in 19665 both came up with radical new suggestions which allow a
fusion of these concepts. Rather than distributing electrons in a planar ring comprising precisely parallel overlap of
2p atomic orbitals, Heilbronner considered what might happen if this array were instead distributed along a Mbius
strip bearing a single half (left or right) twist (Scheme 2).

Scheme 2. Heilbronner's suggestion for a -Mbius conjugated system obtained by electrons located in molecular
orbitals resulting from 2p atomic orbitals distributed around a Mbius strip bearing a single half-twist, rather than a
planar Hckel ring bearing no twist in the orbital basis.

Heilbronner applied Hckel 's equations3 to such a cyclic Mbius ring, finding that a 4n electron system would be
a closed shell species like benzene, with no loss of -electron resonance energy compared to the equivalent
untwisted Hckel ring. A closed shell 4n+2 electron Mbius ring was predicted to be less stable than the untwisted
Hckel counterpart.

Like Hckel before him, Heilbronner did not derive a succinct rule of aromatic stability from these results.
Zimmerman5 was the first to clearly associate the -electron stability of such Mbius rings with an inversion of the
aromaticity rules 1 and 2above. Specifically, populations of 4n electrons result in closed shell (two electrons per
energy level) molecules if the 2p atomic orbitals are distributed along a Mbius strip (rule 1 inverted), whereas 4n+2
-electrons will adopt an open shell (photochemical) distribution in which two of the electrons will now each
occupy a separate molecular orbital (rule 2 inverted).5 By adding a corollary for the anti-aromatic cases, rules 5-8 to
complement 1-4 can be listed;

5. 4n electrons, thermally (closed shell) aromatic and stable with Mbius topology
6. 4n+2 electrons, photochemically (open shell) aromatic and stable with Mbius topology

7. 4n+2 electrons, thermally (closed shell) less stable with Mbius topology

8. 4n electrons, photochemically (open shell) less stable with Mbius topology.

A useful visual mnemonic first proposed by Frost and Musulin 6 for orbital energies of -electron rings based on
inscribing a polygon with one vertex down for the Hckel rules, was memorably extended by Zimmerman 5 to
Mbius systems by redrawing the polygons with one edge down (Figure 2).

Figure 2. Frost-Musulin/Zimmerman Mnemonics for aromaticity selection rules. A six sided polygon is shown for
the Hckel case to coincide with the example shown later in Scheme 5 (red arrows) and an eight-side polygon is
shown for the Mbius case to coincide with the blue arrows in Scheme 5.

Another aspect of Mbius systems which was not directly commented upon by Heilbronner is that a Mbius strip
bearing one half-twist is also chiral, in the sense noted above for the heptahelicene molecule (Figure 1). An ideal
Mbius strip has only a C 2 axis of symmetry present. The specific absence of a plane of symmetry means the mirror
image of a Mbius strip is not superimposable upon the original. In contrast, an ideal planar aromatic molecule of
the Hckel type does have at least one plane of symmetry, referred to here as a C s mirror plane, which means that its
mirror image is superimposable with the original. Thus in Mbius ringed molecules, we do now have a fusion of two
seminal concepts in organic chemistry, that of aromaticity and of chirality!
Scheme 3. An example from Woodward and Hoffmann illustrating how the outcome of a pericyclic reaction
depends on stereoelectronic control mediated by heat or by light.

The next intellectual leap involves a class of organic reaction known as pericyclic, and the recognition by Woodward
and Hoffmann7 that the stereochemical outcome of such reactions was quantum mechanical in origin (Scheme 3).
The original Woodward and Hoffmann argument was based on the symmetries of a subset of the molecular orbitals
called frontier orbitals. This analysis was extended by Longuet-Higgins and Abrahamson 7 to a more formal diagram
showing the correlation of the symmetries of the reactants and product molecular orbitals, and particularly whether
either of the C2 or the Cs symmetry elements noted above were preserved during the course of the pericyclic
reaction. A difficulty in applying such symmetry arguments was the experimental observation that most pericyclic
reactions involved no formal symmetry at all! This difficulty can be overcome by the following procedure.

By considering only the (cyclic) transition state for the pericyclic reaction, one can pose the question: is it
aromatic or not? The advantage is that the aromaticity of a system is robust to minor, desymmetrising,
perturbations caused by the presence of substituents and other non-participating groups.
By equating (ideal) C2 transition state symmetry with Mbius topology and (ideal) C s symmetry with
Hckel topology, one can now apply the aromaticity rules listed above to the transition state.

The first person to associate the -electron stability (aromaticity) of Mbius and Hckel rings with the "allowed" or
"forbidden" nature of the transition states for pericyclic reactions was Zimmerman, 5 via the mnemonic shown above
(Figure 2). Thus the preferred outcome of a pericyclic reaction can be predicted by analyzing whether the transition
state might exhibit Hckel or Mbius aromaticity.7 This simple statement carries some of the most profound and
powerful concepts in modern organic chemistry.

Quantifying Aromaticity

Before introducing a pericyclic reaction which can be used to embody and illustrate these concepts, one more tool is
needed. How does one quantify, or measure, the concept known as "aromaticity". Although much of the discussion
above is couched in terms of the (theoretical) -electron energy, it turns out that accurate measures of aromaticity in
terms of (theoretical or experimental) energies are frustratingly elusive. Many other criteria have been proposed, and
the consensus seems to be that that no single experimental measurement or theoretical calculation can fully,
accurately and uniquely represent aromaticity. It is also evident that experimentally measuring aromaticity for a
transition state will be particularly difficult given its very short lifetime ( 10 -15s)! Instead, recourse has to be taken
to a quantum mechanical calculation rather than direct measurement. Instead of using energies, two other property
calculations are used here for this purpose.

1. The first is inspection of the C-C (or C-heteroatom) bond lengths around the periphery of the ring formed
by the pericyclic transition state. For relatively small sized rings (<14), aromaticity can be related to the
degree of alternation in the bond lengths; no alternation indicates a high degree of aromaticity (and implied
stability), whereas partitioning into short (double) and long (single) bond lengths indicates no aromaticity,
or even anti-aromaticity. This measure is often expressed as r, the difference between the longest and the
shortest C-C bond in the cycle, which typically has a value between 0.00 and 0.04 for an aromatic ring,
and 0.1 for a non-aromatic or anti-aromatic ring.
2. The second measure was introduced by Paul Schleyer,8 and was based on the predicted magnetic properties
of the ring current induced by aromatic electrons. One measurable property of aromatic molecules is the
NMR chemical shift of e.g.protons exposed to such ring currents, which have values characteristic of
"aromaticity" (7-8 ppm relative to tetramethylsilane). To produce a more unique, single metric of
aromaticity, Schleyer proposed instead a calculated property he termed the Nucleus Independent Chemical
shift, or NICS. This property was to be computed at the centre of the ring whose aromaticity needed to be
estimated. By comparison with benzene, a value of about -10 ppm would be deemed aromatic, a value of
around zero would be non-aromatic whilst a positive value of e.g. +20 would be deemed anti-aromatic.
Both these metrics will be used in discussing the example introduced below.
The Electrocyclic Ring Closing Reaction and the Synthesis of a [16] Mbius
Annulene.

The example we have chosen is derived from a remarkable recent synthesis inspired by Heilbronner's 1964 proposal.
From rule 5 above, one can see that a 4n cyclic aromatic (or annulene) is predicted to be Mbius aromatic.
Herges9 and colleagues Ajami, Oeckler, and Simon set out to synthesize a [16] Mbius annulene (n=4) in the
laboratory, with the purpose of subjecting it to experimental tests to see if it really were aromatic. The synthetic
route is set out in Scheme 4, and involves a series of consecutive pericyclic reactions. Herges was able to isolate the
intermediates labeled E in this scheme, and these when subjected to light formed a mixture from which was isolated
one specific product. X-ray crystallography showed that this isomer had the C 2 axis of symmetry required of a
Mbius annulene.

Scheme 4. Herges' scheme for the synthesis of a [16] Mbius ring. Bonds marked with b carry a benzo substituent,
omitted here for clarity.

This synthesis was set as an undergraduate problem class associated with a course on pericyclic reaction given by
the present author, and the students were invited to "push arrows" illustrating the mechanism, the total number
arrows for each step then being used to derive which of the 4n/4n+2 rules listed above is applicable for that step.
One characteristic feature of pericyclic problems is that often, two or more alternatives to the arrow pushing can be
proposed, and normally these alternatives all result in the same analysis of the overall reaction step. So although it
was no surprise that the majority of students in the class illustrated step E to F with the arrows shown in red
(examples of such reactions were contained in the lecture notes for the course), a significant number of students
instead chose to use the arrows shown in blue for this step. The stereochemistry at the bicyclic ring junction in E had
been left undefined in the question, in the hope of provoking the students (and the present author!) to think about the
implications.

A tutorial, in which this problem and possible answers to it were discussed with students, soon revealed that those
students who had invoked the red arrows were led to analyzing the consequences of a 4n+2 rule (n=1), whilst those
who had used the blue arrows were obliged to use the 4n rule (n=3) for this electrocyclic ring opening reaction. It
seemed that for either route, one could regard the reaction as simultaneously following one rule and breaking the
other, and that a contradiction seemed to exist. This certainly led to a lively tutorial.

A [12] Annulene as a Model

Further thought reveals that this specific example can be used to concisely encapsulate many of the concepts
required to fully understand pericyclic reactions. To illustrate these, a reasonably accurate quantum mechanical
model of the two possible transition states for this reaction was computed, and is analyzed in detail below. Several
simplifications of the system was undertaken to enable a practical model to be constructed.

1. The size of the annulene was reduced from [16] to [12] (Scheme 5), it being conformationally much less
complex. This exact reaction is actually known, albeit proceeding in the reverse direction. 10
2. The reaction can be catalyzed by either light (as in Herges' synthesis) or by heat. 9 The theoretical models
were computed for the latter; as exploring the photochemical potential surface is a far more complex task,
with results that may be expected go well beyond the conventional Woodward-Hoffmann approach.

3. Also noteworthy is a fascinating article 11 describing the cis/trans isomerization in the [12] annulene shown
in Scheme 5 as also involving a Mbius transition state.

Two transition states were located for the ring opening reaction. This was done at a level of theory summarized as
B3LYP/6-31G(d), which means use of a density functional procedure with an orbital basis set for the atoms known
as 6-31G(d). This combination is frequently employed nowadays and its properties are well understood.

Scheme 5. A simplified model electrocyclic reaction, showing the plane (C s) or axis (C2) of symmetry which can be
preserved during reaction.

The first transition state in fact corresponds to the three red arrows, maps to the 4n+2 rule, and hence is deemed to
correspond to a Hckel type in which a plane of symmetry (C s) is maintained throughout the reaction. This implies
that the six-membered ring formed by the transition state is Hckel aromatic (rule 1 above). The second transition
state corresponds to the four blue arrows, maps to the 4n rule, and implies that the eight-membered transition ring
has C2 symmetry and is Mbius aromatic (rule 5 above). Are these properties are reflected in the two quantitative
measures of aromaticity described above?
Figure 3. Geometries and transition normal modes for electrocyclic ring opening shown in Scheme 5 for transition
states with Cs and with C2 symmetry. The latter shows the same helical features as previously illustrated in Figure 1.
The supporting information contains 3D rotatable models which can be viewed instead (Java must be installed on
your system to enable this).

Shown in Figure 3 are 3D models visualized using the Jmol applet 12 illustrating the calculated geometries of the two
transition states. The model is animated to illustrate the form of the reaction mode (see supplemental information).
The vibrational mode is computed from a full vibrational analysis of the system, and shows in each case the central
C-C bond periodically breaking or making, in one direction leading to the monocyclic [12] annulene, and in the
other direction to the bicyclic starting material. Various properties of these transition states will be discussed
individually.

The Cs plane and C2 axis of symmetry should be clearly evident from the two geometries. Each vibrational
mode reflects this symmetry.
The stereochemistry of each reaction also reflects its symmetry. The system with C s has cis stereochemistry
at the bicyclic ring junction, whilst that with C2 symmetry has trans stereochemistry.

The Cs system is said to have the two termini of the bond cleaving/forming rotation in opposite directions,
(one clockwise, the other anti-clockwise), a process known as disrotation. The C2 system rotates both
termini in the same direction, i.e.conrotation.

The Cs system forms/cleaves the C-C bond from the same face of the system located on the six-
membered ring, described as suprafacial bond formation/cleavage. The C2 system forms/cleaves the C-C
from the top face of one end of the eight-membered ring, and the bottom face of the other end, described
as antarafacial bond formation/cleavage.

An even more concise summary of these definitions is to refer to the transition state with C s symmetry as
having Hckel form, and to that with C2 symmetry as having Mbius form.
 With the Cs system, the C-C bond lengths around the six-membered (putatively aromatic) ring, starting with
the breaking C-C bond, are 2.22, 1.425, 1.38, 1.42, 1.38 and 1.425. This pattern shows only a little
deviation from the mean of about 1.40, which is typical of the length in benzene itself. Omitting the
actual forming/cleaving bond itself, r is 0.04. Much greater alternation is seen in the values going
around the eight-membered ring; 2.22, 1.46, 1.35, 1.48, 1.34, 1.48, 1.35 and 1.46 (r 0.14) and these
values are more typical of the non-aromatic cyclo-octatetraene ring. A further feature is that the six-
membered ring is almost planar, whilst the 8-ring is highly buckled. These geometries clearly indicate that
for the Csisomer, the six ring is clearly aromatic, in accord with the supposition first suggested above.

In contrast, the values for the six ring in the C 2 system are: 2.37, 1.48, 1.35, 1.47, 1.35 and 1.48 (r 0.13).
This alternating pattern is much reduced for the 8-ring; 2.37, 1.38, 1.42, 1.39, 1.43, 1.39, 1.42 and 1.38 (r
0.04). The former is clearly non-aromatic whilst the latter is aromatic. In addition, the helical nature of
the eight-membered ring can be perceived if compared to that of the helicene shown in Figure 1.

The Cs system has a NICS index of -11.1 ppm at the centroid of the six membered ring, and +0.3 for the
eight membered ring. Bearing in mind a value of about -10.0 for benzene itself, this clearly shows the
smaller ring as the aromatic one.

The C2 system has a NICS index of +2.5 for the six membered ring, and -9.5 for the eight membered ring,
again clearly showing the larger ring now is the aromatic one.

These various measures of aromaticity clearly illustrate how the concept can be applied to transition states for
pericyclic reaction. It also enables one to reconcile how a reaction can apparently both follow one rule, but break the
other in this hybrid electrocyclic reaction. The answer is that only one ring is aromatic in each case, whilst the other
ring essentially just spectates as a non-aromatic participant. In effect, stabilization due to cyclic conjugation occurs
only in the aromatic ring, whilst the spectating ring retains conventional unconjugated bonds.

For those interested in pursuing this topic, an extension of the reaction in scheme 5 to one with two equal sized rings
is presented in the digital interactive version of this article (see Scheme 6).

Conclusions

Chemical reactivity is a complex process, controlled by a variety of influences. Pericyclic reactions are a class which
also often exhibit highly stereospecific behavior, and which are now understood to be subject to quite clear
stereoelectronic influences. These in turn can be traced back to quite simple derivations of the Schroedinger wave
equation, and related to another concept known as aromaticity. To do so fully, requires an understanding of selection
rules expressed in terms of two different forms of aromatic species, the ubiquitous planar Hckel aromatic, and the
relatively new type of Mbius-aromatic. In illustrating the first synthesis of such a stable Mbius system, we
uncover one step in the sequence where the mechanism can be explained in terms of either Hckel or of Mbius
aromaticity of the transition state for the reaction. This exposes a very rare example of a pericyclic reaction which at
first sight appears to simultaneously obey one selection rule, and to disobey another. Reconciling this apparent
discrepancy requires a deeper understanding of how aromaticity as a concept can be applied to such reactions.

References

1. Thomson, J. J. Philosophical Magazine, 1921, 41, 510-538.

2. Writing prior to the discovery of the electron in 1897, Henry Armstrong was the first to give a description
of benzene (and naphthalene) which is recognizable in all regards as encapsulating the modern concept of
an aromatic electron sextet and its more general 4n+2 form. Armstrong, H. E. Proc. Chem. Soc., 1890,
101-105. Ernest Crocker is now recognized as the first to produce a modern more general description for
organic chemistry; Crocker, E. C. J. Amer. Chem. Soc., 1922, 44, 1618-30. For a review, see Balaban, A. T.;
Schleyer, P. v. R.; and Rzepa, H. S. Chem. Rev., 2005, 105, 3436 - 3447.
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4. Heilbronner, E. Tetrahedron Lett., 1964, 1923-8. For a generalization of Heilbronner's derivation for
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S. Phys. Chem. Chem. Phys., 2006, 1775-1777.

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8. Schleyer, P. von R.; Maerker, C.; Dransfeld, A.; Jiao, H.; van Eikema Hommes, N. J. R. J. Amer. Chem.
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9. Ajami, D.; Oeckler, O.; Simon, A.; Herges, R. Nature, 2003, 426, 819-821.

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11. Castro, C.; Karney, W. L.; Valencia, M. A.; Vu, C. M. H, Pemberton, R. P. J. Amer. Chem. Soc., 2005, 127,
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12. The Jmol applet is documented at, and available from http://jmol.sourceforge.net/