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PERKIN
REVIEW
Aromatic interactions

Christopher A. Hunter,*a Kevin R. Lawson,b Julie Perkins a and Christopher J. Urch b

a
Krebs Institute for Biomolecular Science, Department of Chemistry, University of Sheffield,
Sheffield, UK S3 7HF
b
Zeneca Agrochemicals, Jealott’s Hill Research Station, Bracknell, UK RG42 6ET
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Received (in Cambridge, UK) 20th October 2000

First published as an Advance Article on the web 23rd March 2001

Covering: 1950–2000.

1 Introduction
2 Theoretical models
2.1 Van der Waals interactions
2.2 Electrostatics
Fig. 1 Proposed structure of the complex between aniline and
2.3 Induction p-dinitrobenzene.
2.4 Charge-transfer
2.5 Desolvation The Mulliken theory is accepted as a valid description of CT
3 Aromatic interactions in the gas phase complexes.1 The wavefunction of the ground state of a 1 : 1
4 Aromatic interactions in the solid state complex ΨN, is described by eqn. (1), where Ψ0 describes a no
5 Aromatic interactions in biomolecules
6 Aromatic interactions in supramolecular chemistry ΨN = aΨ0(D,A) ⫹ bΨ1(D⫹ ⫺ A⫺) (1)
6.1 Intermolecular interactions
6.2 Intramolecular interactions bond wavefunction and Ψ1 represents a dative bond wave-
7 Quantitative approaches to aromatic interactions function corresponding to the transfer of an electron from D
8 Applications of aromatic interactions (donor) to A (acceptor) with weak covalent bond formation.
9 Conclusions This has been termed an intermolecular electron-pair bond.
10 References The ratio b2/a2 is generally very small in a molecular complex,
but the characteristic CT absorption band is a transition from
1 Introduction the ground state (a2 Ⰷ b2) to an excited state (a2 Ⰶ b2). The
absorption phenomenon which is associated with the exchange
Molecular organisation and molecular interactions are the
of an electron from D to A gives rise to an “intermolecular
basis of the functional properties of most molecules, and a
charge-transfer spectrum”.
detailed understanding of non-covalent chemistry is therefore
The conformations of CT complexes can be predicted by
fundamental to interpreting and predicting relationships
consideration of the quantum mechanical symmetry of
between chemical structure and function. Molecular recogni-
molecular wavefunctions, or experimentally by studying the
tion processes are influenced by many different factors which
dichroism of crystalline complexes.2 There was little quanti-
make their study complicated. Progress requires a quantitative
tative information about these aromatic complexes available
understanding of these different factors. Some key functional
until 1952 when Landauer and McConnell 3,4 presented absorp-
group interactions, such as H-bonding, are well-understood.
tion spectra and equilibrium constants of 1 : 1 complexes
H-bonds are strong, single point interactions with a very
formed between aniline and m-dinitrobenzene, p-dinitro-
well-defined geometry, and their magnitude is determined by
benzene and trinitrobenzene. From a review of crystal
the electrostatic forces between the donor hydrogen atom and
structure data available at that time, the authors put forward a
the acceptor atom. For weaker, less well-defined interactions,
structure for the complexes with the aromatic rings in a stacked
the picture is not so clear. In this review, we focus on one such
arrangement as shown in Fig. 1.
class, aromatic interactions. Here there are multiple points of
The lack of charge-transfer bands in the UV–Visible absorp-
intermolecular contact, the geometry of interaction is variable,
tion spectra of some molecular complexes indicates that there
and there are a vast range of different functional groups that
may be another explanation for the formation of these com-
can be involved. We summarise evidence on the properties of
plexes, i.e. the CT bands are not related to the mechanism of
these interactions from a variety of different sources, and we
interaction, rather are a consequence of different inter-
apologise for necessarily omitting related work.
molecular interactions. If we consider any non-covalent
interaction between two molecules, there are several effects to
2 Theoretical models
be taken into account: (a) van der Waals interactions which are
Chemists have known for a long time that mixing some colour- the sum of the dispersion and repulsion energies. These define
less or weakly coloured solutions of certain substances in the size and shape specificity of the interaction. (b) Electrostatic
non-polar solvents gives intensely coloured solutions without interactions between the static molecular charge distributions.
perturbing the chemical structures of the molecules. The UV– (c) Induction energy which is the interaction between the static
visible absorption spectrum of the mixture shows bands molecular charge distribution of one molecule and the induced
belonging to the two original compounds and also an addi- charge distribution of the other. (d) Charge-transfer which is a
tional broad band in the long-wavelength region—a charge- stabilisation due to the mixing of the ground state (AB) with an
transfer (CT) band. For example, the highly coloured solutions excited charge-separated state (A⫹B⫺) as described above. (e)
formed from mixtures of aromatic amines and nitrohydro- Desolvation: two molecules which form a complex in solution
carbons are attributed to the formation of such CT complexes. must be desolvated before complexation can occur. The solvent

DOI: 10.1039/b008495f J. Chem. Soc., Perkin Trans. 2, 2001, 651–669 651

This journal is © The Royal Society of Chemistry 2001
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Fig. 2 Stacking geometry in a covalently linked cofacial porphyrin

dimer.
Fig. 5 Schematic representation of the effect of substituents on
stacking interactions.
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favourable parallel arrangement and offset stacked describes the

favourable parallel arrangement. This model was used to
Fig. 3 An sp2 hybridised atom in a π-system. account for the observed porphyrin stacking geometry. The off-
set stacked arrangement minimises π-electron repulsion and
maximises the attraction between the σ-framework of one
porphyrin with the π-electrons of the ring immediately below it.
If the aromatic system is polarised by either a substituent
or a heteroatom, stacking interactions can be affected. An
electron donating substituent (e.g. NMe2) increases the
electron density associated with the ring, therefore increasing
the π-electron repulsion. An electron withdrawing substituent
(e.g. NO2) has the opposite effect (Fig. 5). A heteroatom in an
aromatic ring can be electron neutral, electron rich or electron
deficient. When both π-systems are polarised, like polaris-
ations repel and unlike polarisations attract. For unpolarised
π-systems the dominant interaction is π-electron repulsion,
so an electron deficient π-system stabilises the interaction by
decreasing the repulsion.

2.3 Induction
As yet, there is little experimental evidence to suggest that
induction effects are important in aromatic interactions. In
general, these effects will serve to further stabilise a favourable
interaction.

2.4 Charge-transfer
Although charge-transfer bands are commonly observed in
aromatic complexes, this is not always the case. Theoretical cal-
Fig. 4 Electrostatic interactions between π-charge distributions as a culations suggest that these effects make a very small contribu-
function of orientation. tion to the stability of the ground state of molecular complexes.

may compete for recognition sites thereby destabilising the 2.5 Desolvation
complex. Alternatively in polar solvents, solvophobic effects
The flat π-electron surfaces of aromatic molecules are non-
can stabilise the complex.
polar so that solvophobic forces favour stacking. The
In order to understand aromatic stacking interactions, it is
hydrophobic effect and the role of the solvent on aromatic
important to consider the relative effect of each of these forces
interactions will be discussed in detail later.
on the interaction.
Following the experimental observation of CT complexes,
2.1 Van der Waals interactions
there were many attempts to model them theoretically. Chesnut
Aromatic moieties have large planar surfaces, and so a stacked and Mosely 6 used partially-extended Hückel theory to calculate
arrangement maximises the van der Waals contacts. the geometries of charge-transfer complexes which agree well
with the X-ray crystal structures shown in Fig. 6. A feature
2.2 Electrostatics common to all the structures is the presence of a π-bond of
one molecule approximately centred over and parallel to two
In 1990, Hunter and Sanders proposed a model for aromatic
edges of a hexagonal ring of the second molecule. Tetra-
interactions.5 Molecular mechanics calculations on linked
cofacial porphyrin dimers consistently predicted a perfectly cyanoethylene and methylbenzenes were the topic of a different
stacked arrangement of the porphyrin rings, whereas experi- study to calculate the intermolecular interaction energies of the
mental studies show an offset arrangement (Fig. 2). A model complexes.7 The “monopoles bond polarizabilities” procedure
and a method derived from the semi-empirical treatment were
of a π-system was proposed with an aromatic ring described
used. Reasonable agreement with experimental data was
as a positively charged σ-framework sandwiched between two
obtained: the experimental values fall between the two theor-
regions of negatively charged π-electron density (Fig. 3). The
etically determined sets of values. The dipole moment of the
electrostatic interaction between such systems as a function of
dureneⴢTCNE † complex, which is generated due to mutual
orientation is summarised in Fig. 4. The term edge-to-face will
be used to describe the favourable T-shaped, perpendicular
arrangement of aromatic rings. Stacked describes the non- † The IUPAC name for durene is 1,2,4,5-tetramethylbenzene.

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Fig. 8 X-Ray crystal structure of hexafluorobenzeneⴢp-xylene.

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fluorescence excitation spectra of benzene with perylene and

other aromatic species such as anthracene were recorded by
Doxtader et al.21 Correlations between potential energy calcu-
Fig. 6 The arrangements found in X-ray crystal structures of charge-
transfer complexes: (a) naphthaleneⴢTCNE (b) skatoleⴢtrinitrobenzene lations and experimental results suggested that anthraceneⴢ
(c) peryleneⴢfluoroanil (d) anthraceneⴢtrinitrobenzene (e) TCNQⴢ benzene adopted an offset stacked arrangement, but benzene
TMPD. was postulated to sit over the centre of mass of perylene. Levy
et al. also studied the s-tetrazine dimer and concluded the rings
were in a perpendicular arrangement, but the precise structure
was not determined.22

4 Aromatic interactions in the solid state

In 1960, a molecular complex between benzene and hexa-
fluorobenzene was reported.23 Cooling curves of mixtures of
Fig. 7 Geometries of s-tetrazine dimers: (a) stacked (b) edge-to-face. the two compounds showed the formation of a 1 : 1 complex
which was attributed to charge-transfer interactions. However,
electronic polarisation of the molecules was calculated to be no charge-transfer band was found in the UV spectrum. The
1.26 D which exactly matches the experimentally determined structure of the complex was determined by neutron diffraction
value. experiments and showed long stacks of alternating benzene
There have been various attempts to model the benzene and hexafluorobenzene molecules. X-Ray crystal structures
dimer theoretically by Linse,8 Jorgensen and Severance,9 Jaffe of hexafluorobenzene and a series of methylated benzenes
and Smith 10 and Kollman and co-workers.11 Schlag and co- have been determined and all show similar interactions to
workers used gas phase ab initio techniques and initially pre- hexafluorobenzeneⴢbenzene (Fig. 8).24
dicted an edge-to-face arrangement as the optimum structure The formation of such stacks can be explained in terms of
with an interaction energy of ⫺6.3 kJ mol⫺1.12,13 However, a the quadrupole moment of the two molecules. The quadrupole
later study revealed that there are two minima in the potential moment of benzene is large and negative (⫺29.0 × 10⫺40 C m2),
energy surface of the dimer.14 The more stable was found to be and due to the electronegativity of fluorine, the quadrupole
the offset stacked structure. This structure was also found by moment of hexafluorobenzene is large and positive (31.7 ×
Jaffe and Smith.15 The benzene dimer was studied experi- 10⫺40 C m2). This is represented schematically in Fig. 9. A
mentally using molecular beam spectroscopy, and an edge- stacked arrangement of benzene and hexafluorobenzene
to-face dimer was proposed.16,17 The most stable calculated maximises the electrostatic interaction energy, where a positive
benzene dimers were also in a perpendicular arrangement. quadrupole moment is found parallel and next to a negative
The s-tetrazine dimer was studied experimentally by Levy quadrupole moment (Fig. 9).
et al.,18,19 and two orientations were observed: stacked and A comprehensive study of the packing patterns of planar
edge-to-face (Fig. 7). The stacked dimer was predicted to be aromatic hydrocarbons was carried out by Gavezzotti.25,26
the most stable by calculation, and this geometry agrees well Geometrically similar molecules crystallise with the same basic
with the experimental data. Price and Stone studied the packing motif, and there are only a small number of well-
s-tetrazine and benzene dimers and various heterodimers.20 The defined structural types: herringbone, sandwich-herringbone,
Buckingham–Fowler model was used to investigate dimers sandwich-herringbone β and sandwich-herringbone γ depend-
such as benzeneⴢacetylene, s-tetrazineⴢacetylene, s-tetrazine ing on the relative orientation of the molecular planes in the
dimer, s-tetrazineⴢbenzene, benzene dimer, anthraceneⴢbenzene crystal which is reflected in the shortest cell axis. Sandwich-
and peryleneⴢbenzene. The electrostatic energy was shown herringbone structures form molecular pairs, which are organ-
to be the dominant force in determining the structures of the ised in a herringbone pattern (Fig. 10). Linear correlations of
complexes. packing energy with the number of valence electrons and
molecular surface were obtained. The slopes of both plots were
larger than for structures containing heteroatoms, i.e. aromatic
3 Aromatic interactions in the gas phase
hydrocarbons form very tightly packed crystals as indicated by
Klemperer et al. used the electric deflection of molecular beams a higher packing coefficient (0.748 cf. 0.712 for heterocycles).
to study the benzene dimer.16 The dimer was found to be polar, Gavezzotti proposed that the link between molecular and
and this polarity was attributed to the presence of a permanent crystal structure is the ability of a molecule to employ C–C and
electric dipole moment in the ground vibrational state. There- C–H interactions. C–C interactions are optimised in a stacked
fore the equilibrium geometry of the benzene dimer must be of conformation at van der Waals contact separation and C–H
a symmetry allowing a permanent electric dipole, an edge-to- interactions are most effective between edge-to-face molecules.
face geometry. All reasonable geometries in which the planes of A model for predicting structures was devised based on the
the benzene molecules are parallel (stacked) give a non-polar number and positioning of C and H atoms in the molecules.27,28
dimer and therefore were eliminated. A coarse study of hexa- Part of the molecular surface was defined as stack promoting
fluorobenzeneⴢbenzene identified a stacked arrangement.17 The (core atoms and 50% of the rim carbon atoms) and the rest as

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glide promoting (the other 50% of the rim C atoms and all double helix is 50% dissociated and has been used to determine
hydrogen atoms). The glide to stack ratio as a function of the the effect base stacking has on helix stability. Tm increases with
total molecular surface provides a predictive map to go from increasing GC content but depends strongly on sequence as
molecular to crystal structure and was used to predict the well as composition. Helix assembly takes place via a co-
crystal structures of several hydrocarbons which are not yet operative zipper mechanism, where the initial formation of the
known. first few base pairs is an energetically unfavourable process.
However once this nucleus is created, new base pair formation
5 Aromatic interactions in biomolecules leads to favourable contributions to the free energy.30 Zimm
used the theory of melting to try to determine a value for the
Aromatic stacking interactions are widespread in nature. The
“stacking free energy”—the free energy gained when base pairs
classic example is base stacking in DNA which was first recog-
are stacked on each other in the helical arrangement.31,32 The
nised in the structure determined by Watson and Crick in
free energy was estimated to be ⫺29 kJ mol⫺1 per base pair and
1953.29 The melting temperature Tm is the point at which a
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is therefore the major free energy contribution stabilising the

double helix. Interactions between the individual bases and
modified bases in aqueous solution have been studied by several
groups.33–35 The general conclusion is that the association of the
bases can be largely attributed to stacking of the rings. Solvent
effects have also been investigated using the Raman laser
temperature-jump technique,36 again with the conclusion that
stacking interactions between the bases dominate the thermo-
dynamics of helix formation. The “dangling end” technique
involving an oligonucleotide with a terminal unpaired base has
been used in various studies to estimate what one stacking
interaction contributes towards helix stability.37 More recently
Guckian et al. have looked at aromatic stacking affinities in the
context of DNA by substituting the terminal base for aromatic
hydrocarbons such as benzene, naphthalene and pyrene.38
Generally, increasing the size of the aromatic surface increased
the melting temperature of the oligonucleotide.
Nucleic acids play a central role in cellular metabolism and
so are a common target for drugs designed to prevent cell
replication. Aromatic stacking interactions play a pivotal role
in drugs which intercalate with DNA. Intercalation was first
observed by Lerman when he studied the complex between
DNA and acridine.39 A mechanism was proposed whereby the
acridine could fit between the base pairs of DNA without dis-
rupting the hydrogen bonding motif. This process however
causes a change in the physical characteristics of DNA as the
helix unwinds, and the bases unstack to allow the intercalator
in. This leads to an increase in length of the DNA and a disrup-
tion of the regular helical structure (Fig. 11). A variety of DNA
intercalators have been found to reduce tumour growth in
animals and man, and so these compounds are commonly used
as anticancer agents.
In 1985, Burley and Petsko analysed side-chain interactions
in proteins.40 Two aromatic residues were considered to interact
if the distance between phenyl centroids was less than 7 Å. The
results showed 60 percent of aromatic side chains in proteins
were involved in aromatic pairs, and 80 percent of these were
involved in networks of three or more interacting side chains.
The most favoured distance between the rings was 5 Å, and the
Fig. 9 Schematic representation of the quadrupoles of benzene and most favoured dihedral angle was 90⬚. Non-bonded potential
hexafluorobenzene, and the arrangement in the crystal which aligns energy calculations were carried out and showed a typical
opposite charges. phenyl–phenyl interaction has an energy of between ⫺4 and

Fig. 10 Packing of naphthalene (HB, left), benzperylene (SHB, middle) and hexabenzocoronene (γ-SHB, right).

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Fig. 11 The DNA double helix in the absence (a) and presence (b) of
an intercalator (red). Fig. 13 Cyclophane complexes used to study substituent effects by
Diederich.

of 2,6-disubstituted naphthalene derivatives by cyclophanes in

d4-methanol (Fig. 13). The interaction between host and guest
was most favourable for guests with electron withdrawing
substituents such as X = CO2H, NO2 and CN and least favour-
able for those with electron donating substituents such as
X = CH2OH, NH2 and CH3.42 The cyclophane can be thought
of as a donor host with 4 phenyl rings substituted with electron
donating methoxy groups. The most stable complexes were
formed with electron poor guests, and this suggests that electro-
static interactions are the major factor determining the stability
of the complexes. No charge-transfer bands were observed in
the UV–visible absorption spectra, indicating CT played no
part in the stability of such complexes. This work demonstrated
the importance of electronic complementarity in the complex-
ation of aromatic guests. Guests prefer the axial arrangement
since this allows highly solvated polar substituents to poke
out into the surrounding solvent minimising any unfavourable
desolvation. Analysis of the complexation induced shifts of the
protons of the guest implied that naphthalene molecules bear-
ing electron accepting substituents are located more deeply
within the cavity than those with donor substituents. The
experiments were repeated in d6-dimethyl sulfoxide and the
same trends in complexation strength were observed which
suggests the differences between guests are not due to solvent
effects.
The effect of solvent on aromatic interactions was also
studied by Smithrud and Diederich using the complexation of
Fig. 12 (a) The electrostatic interaction between two benzene rings as
a function of orientation (shaded = attractive, unshaded = repulsive). pyrene by a different cyclophane (Fig. 14).43 The association
(b) The geometries of phenylalanine side chain interactions found in constants were determined in 18 solvents of differing polarities.
protein X-ray crystal structures. A linear relationship was obtained between the stabilities of the
complexes and the solvent polarity described by the empirical
⫺8 kJ mol⫺1. The distribution of aromatic rings throughout the ET(30) parameter. Diederich’s model describes the solvent
protein was also analysed, and aromatic residues and therefore properties which appear to be most important in determining
aromatic pairs were not found in regions where the polypeptide the strength of apolar host–guest complexation. Binding is
chain is disordered. It was therefore suggested that aromatic strongest in polar solvents possessing low molecular polaris-
interactions may form nucleation sites in the protein folding ability and high cohesive factors. Solvents with high cohesive
pathway. Hunter calculated the electrostatic interaction interactions interact more strongly with “like” bulk solvent
between two benzene molecules as a function of orientation than with the apolar surfaces of the host and guest molecules,
and compared it to the observed geometries of interacting so when complexation takes place, free energy is gained upon
phenylalanine rings in proteins with good correlation.41 The the release of surface-solvating molecules to bulk solvent. Thus
perfectly stacked arrangement was not observed, but a range of water is the best solvent for apolar binding.
edge-to-face and offset stacked geometries were found (Fig. 12). Whitlock et al. designed a macrocyclic host to bind nitro-
phenol (Fig. 15), K = 9.6 × 104 M⫺1.44,45 A combination of
6 Aromatic interactions in supramolecular chemistry aromatic stacking interactions and hydrogen bonding was
responsible for tight binding. Use of a more flexible linker
In the mid 1980s, the concept of supramolecular chemistry,
reduced the binding constant to 6 × 103 M⫺1 indicating the
“chemistry beyond the molecule”, came into being, and the
importance of preorganisation.
synthetic molecular receptors which were developed appeared
Dougherty and co-workers used the system shown in Fig. 16
to provide ideal systems for the study of quantitative structure–
to examine the contributions of aromatic and ion-quadrupole
activity relationships in non-covalent interactions.
interactions to complexation in aqueous media.46 Hosts 1 and 2
have similar dimensions and comparable degrees of pre-
6.1 Intermolecular interactions
organisation. The rigid framework ensured the charged groups
Ferguson and Diederich studied the complexation of a series could not interact with the guests, and therefore any difference

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Table 1 Association constants K (M⫺1) for Dougherty’s cyclophane

hosts with guests 3–11 in aqueous solution at 295 K

K/M⫺1

Guest Phenyl host 1 Cyclohexyl host 2

3 1.0 × 104 2.2 × 104

4 1.1 × 104 2.0 × 104
5 3.8 × 104 3.0 × 104
6 4.7 × 104 4.6 × 104
7 5.5 × 104 1.0 × 105
8 1.4 × 103 1.6 × 103
9 2.1 × 103 3.8 × 103
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10 4.0 × 105 4.7 × 104

11 2.0 × 105 2.7 × 104

Fig. 14 Dependence of the free energy of complexation of the cyclo-

phaneⴢpyrene complex, ⫺∆G (kJ mol⫺1), on the solvent polarity, ET(30)
(kJ mol⫺1).

Fig. 15 Two views of the complex formed between Whitlock’s bicycle

and p-nitrophenol.

in binding could be ascribed to interactions with the spacer

group. If the hydrophobic effect was dominant, then the
cyclohexyl derivative should show the strongest binding (cyclo-
hexyl is more hydrophobic than phenyl). The phenyl deriv-
ative should be a better host, if aromatic interactions are Fig. 16 Dougherty’s phenyl host 1 (X-ray structure) and cyclohexyl
important. The results of binding studies are summarised in host 2 which bind guest molecules 3–11 in water.
Table 1.
Both hosts bind the electron deficient quinoline and iso- action of the positive charge with the π-electrons: the cation–π
quinoline units 3–7 more strongly than the electron rich indole effect.
units 8 and 9. This was evidence that electrostatics play an The directionality of the cation–π effect was studied by
important role in the binding. The phenyl host 1 bound the Schwabacher and co-workers.47 The cationic 12 and anionic 13
charged guests 10 and 11 more strongly than the cyclohexyl hosts in Fig. 17 were designed to study the interaction of
derivative 2. Comparison of the results for isostructural guest charges with the edge of a bound aromatic ring. Schneider and
pairs showed this enhancement was due to charge and not to co-workers had previously shown enhanced binding of aro-
steric or hydrophobic effects. The enhanced binding of cations matic guests by cationic cyclophanes over anionic analogues.48
10 and 11 by the phenyl host 1 was therefore due to the inter- The association constants for dihydroxynaphthalenes 14 and

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Table 2 Association constants K (M⫺1) for guests 14–17 with

Schwabacher’s cyclophane hosts

K/M⫺1

Cationic host (12) Anionic host (13)

D2O–CD3OD D2O–CD3OD
Guest D2O (60 : 40) D2O (60 : 40)

14 7 526 25
15 3 204 18
16 23 10 164 36
17 67 1282
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Fig. 18 Hamilton’s thymine receptors. (a) Ester substituents lead to a

stacking interaction. (b) Alkoxy substituents prevent stacking. (c) The
geometry of the stacking interaction in (a). (d) The alignment of
charges which leads to the attractive interaction in (a).

Fig. 19 The complex formed between Rebek’s cleft 21 and pyrazine

22.
Fig. 17 Schwabacher’s cationic (12) and anionic (13) cyclophane
complexes and aromatic guests 14–17.

15, tropolone ‡ 16 and acenaphthalene 17 are shown in Table 2.

The association constants are larger for the anionic host which
implies that the positive edge of the guest interacts more
favourably with the negative walls of the anionic host. With the
larger aromatic guests tropolone 16 and especially acenaphthal-
ene 17, where the edge of the aromatic ring is much closer to the
charged junction, significant increases in association constants
were observed.
In 1987, Hamilton and co-workers reported the synthesis of
a class of thymine receptors which showed edge-to-face or
stacked aromatic interactions depending on the electronic
properties of the substituents.49,50 Macrocycle 18 formed a 1 : 1
complex with 1-butylthymine 20 (K = 570 M⫺1 in chloroform).
NMR studies indicated a stacked geometry which was con-
firmed by an X-ray crystal structure (Fig. 18(a) and 18(c)).
MNDO calculations on 2,7-dimethoxynaphthalene-3,6-dicarb-
oxylic acid and thymine indicated a precise alignment of five
pairs of oppositely charged atoms (Fig. 18(d)) which confirmed
the importance of complementary electrostatic interactions in
face-to-face stacking. Tetraether macrocycle 19 bound more Fig. 20 Complexes used to investigate stacking interactions with
weakly (K = 138 M⫺1). MNDO calculations indicated a mis- adenine.
match in the charge distributions for this system, and NMR
spectroscopy and the X-ray crystal structure showed that an form. Quinoxaline 23 showed a 15-fold enhancement in binding
edge-to-face interaction is used to avoid stacking (Fig. 18(b)). (K = 2.3 × 104 M⫺1), due to a stacking interaction with the
Rebek and Nemeth designed a molecular cleft (21) to bind anthracene group which was revealed by upfield shifts of the
aromatic guests (Fig. 19).51 The binding of 21 to heterocyclic quinoxaline protons.
diamines was studied using 1H NMR spectroscopy. For Rebek et al. later developed a synthetic system that can
pyrazine 22, the binding constant was 1.4 × 103 M⫺1 in chloro- recognise adenine using Watson–Crick or Hoogsten hydrogen
bonding and aromatic interactions (Fig. 20).52 Kemp’s triacid
‡ The IUPAC name for tropolone is 2-hydroxycyclohepta-2,4,6-trien-1- formed the basis of the receptor which could be substituted
one. with a variety of aromatic groups of varying size and electronic

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Table 3 Association constants for complexation of adenine by hosts Table 4 Association constants K (M⫺1) for complexation of TNF by
24–28 in chloroform at 298 K molecular tweezers 30–33

24 25 26 27 28 K/M⫺1

K/M⫺1 75 100 120 440 240 Compound CDCl3 d8-THF C4D8O2

30 149 28 47
properties. The results of NMR binding experiments are 31 320
summarised in Table 3. The phenyl and naphthalene systems 32 475
show only a small increase in the association constant com- 33 697
pared to the control methyl amide, whereas anthracene shows a
nearly six-fold increase in binding constant which corresponds use of donor solvents, THF and 1,4-dioxane, which solvate
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to a stacking interaction of 4.2 kJ mol⫺1. TNF better than chloroform greatly reduced the association
Chen and Whitlock first defined molecular tweezers as constants.
synthetic receptors containing two complexing aromatic Zimmerman and co-workers covalently linked the tweezers
chromophores connected by a single spacer.53 Bisfunctional to silica to construct chemically bonded stationary phases for
derivatives of caffeine 29 showed an increase in association HPLC.56,57 The retention times of several nitro-substituted
constant relative to simple caffeine derivatives when complexed polycylic aromatic hydrocarbons were measured. The HPLC
with planar aromatic guests such as 2,6-dihydroxybenzoate and chromatogram in Fig. 23 shows how increasingly electron-poor
1,3-dihydroxy-2-naphthoate (Fig. 21). aromatics are retained longer on the column. With such good
Since then, molecular tweezers have been the subject of separation, this system was proposed as a potential tool
an extensive study by Zimmerman. In 1987, he described a for analysing nitro-polyaromatic hydrocarbons, an important
molecular tweezer in which a rigid spacer enforced a syn- class of environmental pollutants. Good correlation of HPLC
cofacial arrangement of two acridine chromophores as shown and solution enthalpies were obtained with these systems.
by the X-ray structure in Fig. 22(a).54 The spacer holds the The tweezer motif is still being used by Zimmerman et al. to
chromophores approximately 7 Å apart, ideal for a planar organise dendritic systems.58
aromatic guest. Complexation studies were carried out in Nolte and co-workers used hydrogen bonding and aromatic
chloroform solution by 1H NMR spectroscopy, and the tweezer interactions to design a series of molecular clips.59 Separation
shown in Fig. 22(a) binds 2,4,7-trinitrofluoren-9-one (TNF) of the effects of hydrogen bonding and aromatic interactions
with an association constant of 172 M⫺1. Large upfield shifts on the binding of resorcinol derivatives was carried out by syn-
observed for the TNF resonances suggest the TNF carbonyl is thesising a series of clips with different numbers of aromatic
directed towards the spacer. Both the mono- and di-acridine
control compounds 34 and 35 showed association constants
of less than 5 M⫺1 with TNF, indicating both acridines are
required and that the rigidity of the spacer plays an impor-
tant role (Fig. 22(c)). Electron donor–acceptor effects were
probed using the tweezers 30–33 and the results are shown
in Table 4 (Fig. 22(b)).55 As the electron density of the host
π-system increases, the association constant increases. The

Fig. 23 HPLC chromatogram for a tweezer functionalised stationary

Fig. 21 Whitlock’s molecular tweezer. phase compound.

Fig. 22 (a) X-Ray structure of Zimmerman’s molecular tweezer. (b) The structures of tweezer derivatives 30–33. (c) Control compounds 34 and 35.

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Table 5 Association constants for receptor 36 with benzoic acid

derivatives in chloroform at 298 K

Guest K/M⫺1

3-Ethoxycarbonylbenzoic acid 1.47 × 103

2-Toluic acid 3.52 × 104
Benzoic acid 6.00 × 104
4-Ethoxybenzoic acid 1.53 × 105
3,4-Methylenedioxybenzoic acid 1.58 × 105
3,4,5-Trimethoxybenzoic acid 2.41 × 104
3-Dimethylaminobenzoic acid 8.21 × 105
4-Dimethylaminobenzoic acid 1.56 × 106
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Fig. 25 Crego’s clefts bind benzoic acid derivatives.

3,4-methylenedioxybenzoic acid) indicating that the system is

more complicated.
Moore and co-workers prepared hexakis(phenylacetylene)
molecules (PAMs) with varying degrees of electron withdraw-
ing (ester) and donating (alkyl ether) substituents and studied
their aggregation properties by 1H NMR in chloroform
(Fig. 26(a)).62,63 The chemical shifts of the aromatic protons
depend strongly on concentration, and dimerisation through
aromatic stacking interactions was proposed to account for
this. Compounds 37, 38 and 39 show dimerisation constants of
60, 18 and 26 M⫺1 respectively. Compounds 40 and 41 show no
aggregation behaviour. These results indicate that the aro-
matic substituents have a significant influence on the stacking
interaction. tert-Butyl ester substituents prevent aggregation,
indicating that the interaction is due to face-to-face stacking
which is hindered by the bulky groups. Non-planar pentakis-
and heptakis-(phenylacetylene) molecules also have reduced
association constants. Tobe et al. designed a PAM system
capable of heteroaggregation and binding metal ions (Fig.
26(b)).64 Compounds 42 and 43 form a 1 : 1 heteroaggregate but
42 does not self-associate. The electron withdrawing cyano-
Fig. 24 Nolte’s molecular clips and the complex formed with catechol. substituents appear to enhance aromatic stacking interactions
in the heteroaggregate.
side-walls (Fig. 24).60 The host with no walls can only bind
6.2 Intramolecular interactions
resorcinol by hydrogen bonding (K = 25 M⫺1). With one cavity
wall, the association constant increased to 65 M⫺1, but a second Moore and co-workers designed oligomers based on the
wall dramatically increased the association constant to 2600 PAMs 65 and showed that these phenylacetylene oligomers fold
M⫺1. Changing the methoxy substituent on the cavity walls to a up in a process driven by solvation (Fig. 26(c)). Hypochromic
methyl group and then to a hydrogen decreased the association effects measured in several solvents were used as a measure
constants, and the differences were attributed to a decrease in of conformational changes. When n = 8 in acetonitrile, the
the strength of the aromatic stacking interaction. Naphthalene oligomers formed an ordered structure consistent with a helix.
1
side-walls were introduced in an effort to increase the van der H NMR studies in chloroform showed negligible changes in
Waals contacts between the host and guest. However, this chemical shift with increasing chain length, whereas in
decreased the association constants, presumably due to an acetonitrile, upfield shifts were observed for the phenyl protons,
increase in the π-electron repulsion between host and guest, and these increased dramatically as n increased from 8 to 14.
indicating it is electrostatics rather than van der Waals forces The helical structure minimises interactions of the hydrocarbon
which play the pivotal role in determining the magnitudes of backbone with the solvent and maximises intramolecular
the aromatic stacking interactions here. aromatic stacking.
A cleft type receptor for aromatic acids was reported by Iverson et al. have also used aromatic stacking interactions
Crego et al. (Fig. 25).61 The receptor 36 relies on stacking to dictate the secondary structure of synthetic oligomers in
interactions and hydrogen bonding and binds a variety of solution.66 The system consists of electron acceptor (naph-
substituted aromatic acids and amides. Generally, the binding thalene-1,8 : 4,5-tetracarboxylic diimide) and electron donor
constants increase with increasing π-electron density on the (1,5-dialkoxynaphthalene) units, selected because the monomers
guest (Table 5). However, there are some anomalies (e.g. with are known to form a stable complex in water (K = 130 M⫺1).

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Fig. 27 Structure of the co-crystal of a 1,4,5,8-naphthalenetetra-

carboxylic diimide and a 1,5-dialkoxynapthalene.

phase synthesis. Spectroscopic evidence for n = 2 and 3 is

consistent with a pleated structure where the aromatic rings are
all stacked as shown.
The electron acceptor unit was also used in the synthesis
of a tetraintercalator connected by four tetrapeptide linkers
(Fig. 29).67 One lysine residue was placed on each segment
to provide electrostatic attraction to DNA. Hypochroism,
unwinding studies, kinetics, DNAase and chemical footprinting
show that the polyintercalators have a preference for GC
sequences, and a cooperative mode of binding was proposed.
As we have already seen, the hydrophobic effect has a
significant influence on aromatic interactions, water prefer-
ring to interact with itself rather than with aromatic surfaces.
Newcomb and Gellman carried out a series of experiments to
investigate this effect for two covalently tethered aromatic
groups. A comparison of the stacking tendencies of hydro-
carbon (phenyl and naphthyl) and heterocycle (adenine) rings
in aqueous solution was carried out using 1H NMR spectro-
scopy to study the conformational properties of carboxylate
derivatives 44–48 (Fig. 30).68 Large negative shifts of the
adenine protons of 44 were observed compared with the control
47. This is indicative of an intramolecular aromatic inter-
action in 44. In contrast, 45 and 48 have similar spectra which
indicates that there is no intramolecular interaction for the
dinaphthyl derivative. An X-ray structure of a phenyl derivative
49 showed the phenyl rings splayed far apart. In 46, negative
shifts on both rings indicate significant stacking. DMSO
destroyed the interaction. If the intramolecular stacking were
due solely to the hydrophobic effect, then 45 would exhibit a
Fig. 26 (a) Moore’s macrocyclic phenylacetylene molecules (PAMs).
stacking interaction. The results are most consistent with the
(b) Tobe’s macrocyclic PAMs. (c) Moore’s open chain PAMs which fold
in acetonitrile. alignment of partial positive and negative charges on neigh-
bouring groups as the main force influencing the stacking
interactions.
A co-crystal of the two monomers showed the electron donors Naphthyl units connected by a flexible linker were prepared
and acceptors in an alternating stack (Fig. 27). Molecular to further probe hydrophobic collapse.69 The three atom linker
mechanics together with the X-ray crystal structure were used previously used forced a near parallel arrangement, but the four
to determine an ideal backbone length to allow the electron atom linker in 50 allowed different approaches of the aromatic
donor and acceptor units to be linked in a chain but still form moieties. An X-ray crystal structure of 50 showed an edge-to-
a stacked arrangement in solution: -aspartic acid residues face arrangement of the naphthyl rings, and 1H NMR experi-
were used. The “aedemers” in Fig. 28 were prepared by solid ments showed that the naphthyl rings are in close proximity in

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Fig. 28 Structure of Iverson’s aedemers (n = 1, 2, 3) and a cartoon of the folded solution structure.

Fig. 29 Polyintercalators based on diimide amino acid oligomers (n = 1, 2, 3, 4).

aqueous solution. The chemical shift differences between 50 and 0.5 ppm on both the anthracene and dinitrophenyl rings.
and 51 in benzene were very similar to those in water which A stacked intramolecular complex was proposed. If van der
suggests that the hydrophobic effect has little influence on the Waals interactions were dominant in the complex, the greatest
folding of this molecule. effect would be in the symmetrical anthracene derivative, as it
Kollman and co-workers recently used a combination of would provide the largest van der Waals contact. No charge-
modelling and NMR studies on similar compounds with differ- transfer bands in the UV spectra were observed. Hence the
ent results.70 The possible geometries of the indole derivative 52 interaction was attributed to electrostatic quadrupole inter-
were calculated theoretically. The linker allows the molecule to actions, as the quadrupole moments of the dinitrophenyl and
adopt edge-to-face, offset stacked, face-to-face stacked and anthracene groups have opposite signs.
non-stacked conformations. The calculations suggested that the Breault et al. used metal tris(bipyridine) complexes 59 and 60
edge-to-face and non-stacked conformations are the most to investigate the influence of solvent on aromatic inter-
stable in water. 1H NMR studies on 52 showed a larger popu- actions.72 The differences between the chemical shifts of the
lation of the edge-to-face stacked conformation in water than bipyridine protons in the presence of pendant alkyl and
in DMSO at 22 ⬚C. aromatic esters were used to quantify the aromatic interaction
Jimenez-Barbero used a similar approach to investigate as a function of solvent (Fig. 32). Large upfield shifts were
stacking interactions in benzene using ester linked aromatic observed in polar solvents such as water, and the magnitude of
units 53–58 (Fig. 31).71 The 1H NMR spectrum of the the shift decreased as the solvent polarity decreased. This is
symmetrical diesters 54 and 56 and corresponding control consistent with the solvophobic description of aromatic inter-
monoesters 53 and 55 are very similar, indicating there is no actions as seen in the Diederich cyclophane system.73 However,
intramolecular interaction. However, the spectrum of the as the solvent polarity was decreased further, the strength of the
unsymmetrical diester 57 shows upfield shifts of between 0.1 aromatic interaction went through a minimum in DMSO and

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Fig. 30 Compounds used to probe intramolecular aromatic interactions in water.

Fig. 31 Compounds used to probe intramolecular aromatic interactions in benzene.

then started to increase again, and in chloroform the inter- Table 6 Barriers to rotation for substituted 1,8-diarylnaphthalene
action is comparable to that in water. These results suggest that molecules
in non-polar solvents, electrostatic interactions become domin-
ant and lead to significant attractive interactions between the Substituent ∆G‡/kJ mol⫺1
aromatic rings.
Stoddart and co-workers have used aromatic stacking inter- OMe 58.2
actions to direct the synthesis and influence the properties of a Me 60.2
H 61.5
large number of catenanes, pseudorotaxanes and rotaxanes. Cl 64.9
Initially a 1 : 1 complex was observed between di-p-phenylene- CO2Me 70.7
34-crown-10 and paraquat dication (Fig. 33(a)).74 The complex NO2 72.4
between a tetracationic ring based on paraquat and 1,4-
dimethoxybenzene was also crystallised (Fig. 33(b)), and this
7 Quantitative approaches to aromatic interactions
revealed the aromatic stacking interactions that are responsible
for complexation. The interactions in these complexes formed Cozzi and Siegel and co-workers used substituted 1,8-diaryl-
the basis of the template directed synthesis of a [2]catenane naphthalene molecules to measure the barrier to rotation of the
(Fig. 33(c)).75 This initial design led to higher order catenanes, phenyl rings in chloroform using dynamic NMR (Fig. 35(a)),
the largest being a [7]catenane which was synthesised under and the results are shown in Table 6.79 The activation energy
high pressure.76 Pseudorotaxanes followed and stoppering for the isomerism provides a measure of the strength of the
the ends of the thread of the pseudorotaxane resulted aromatic interaction between the stacked phenyl rings in the
in [2]rotaxanes. Again, higher order pseudorotaxanes and ground state. These results were plotted against Hammett sub-
rotaxanes were synthesised and characterised.77 A summary of stituent constants, and a linear relationship was found which
the approach to pseudorotaxanes, rotaxanes and catenanes is indicates that electrostatic effects are the most important factor
shown in Fig. 34.78 in this system. There was no UV–visible spectroscopic evidence

662 J. Chem. Soc., Perkin Trans. 2, 2001, 651–669

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for a charge-transfer interaction between the phenyl rings. The

experimental evidence that the barrier increases on passing
from an electron donating group to an electron withdrawing
group as substituent led to the conclusion that a significant
polar π-interaction exists between the phenyl rings.80 When
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Fig. 32 Metal complexes for studying solvent effects on aromatic Fig. 33 Host–guest complexes formed by the Stoddart macrocycles
interactions. ∆δ = δ(H3 in 59) ⫺ δ(H3 in 60). (a) and (b), and the corresponding [2]catenane (c).

Fig. 34 Synthetic approaches to rotaxanes (b) and catenanes (c) using aromatic stacking interactions to organise the key pseudorotaxane
intermediate (a).

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Fig. 35 (a) Dynamic equilibrium used to quantify substituent effects

on aromatic stacking interactions between substituted phenyl rings
(X = OMe, Me, H, Cl, CO2Me, NO2). (b) Fluorination of the 1,8-
diarylnaphthalene derivatives changes the quadrupole moment of the
aromatic ring and consequently the trends in stacking interaction
energy.

Fig. 37 The double mutant cycle used to quantify the tyrosine–

tyrosine interaction in barnase. The geometry of interaction in the
X-ray crystal structure of the wild type protein is shown.

the barriers to rotation as a function of substitution of X.

These results suggest that it is electrostatics that govern the
magnitude of the stacking interaction in this system.
Wilcox and co-workers constructed a molecular balance
capable of measuring edge-to-face aromatic interactions using
conformational isomerism as shown in Fig. 36.82 In the
folded conformation, the edge of ring b lies over the face of
ring c (Fig. 36(a)). In the open conformation, rings b and c
are remote (Fig. 36(c)). While both conformations include an
interaction between rings b and d, this does not perturb the
relative populations. The two conformations interconvert by
slow rotation at room temperature. Deviations from a 1 : 1
ratio of states provide a measure of the b–c interaction.
When Y = H the folded state is preferred, substitution with a
Fig. 36 Wilcox’s torsion balance used to quantify the interaction
between rings b and c. The X-ray structure of the folded conformation
methyl group shifts the equilibrium slightly, but a methoxy
is shown (a). The approach was used to measure interactions of a range group has no effect. When Y = I, CN or NO2, there is an
of functional groups with the face of an aromatic ring (c). enhanced preference for the folded state which suggests that
electrostatic effects are important in the edge-to-face inter-
substituents were present on both aromatic rings, a linear action. However, phenyl, cyclohexyl and isopropyl groups all
relationship was obtained between the barrier to rotation and show similar affinities for the face of the aryl ring c.83 A
the sum of the Hammett substituent constants. If a CT range of electron donating and withdrawing groups were
interaction were dominant then the donor–acceptor inter- used (X = NH2, OH, CH3, I, Br, CN, and NO2). The folding
action would be most favourable, followed by the acceptor– energies of the isopropyl and phenyl esters were found
acceptor and finally the donor–donor interaction. The to be ⫺2.0 ± 0.4 and ⫺1.3 ± 0.4 kJ mol⫺1 respectively for
experimental results show that this is not true: the most all X substituents. This result suggests that electrostatic
favourable interaction is acceptor–acceptor followed by forces are not important and that London dispersion forces
donor–acceptor and finally donor–donor interactions. The are more important in governing the edge-to-face inter-
most reasonable explanation for such a trend is that the action. However, these systems are not fully understood as the
electron withdrawing groups decrease the repulsive inter- populations of the two states are unaffected by changes in
actions between the π-electron density of the phenyl rings, when solvent.
they are in a forced stacked conformation. Following the observations by Burley and Petsko 40 concern-
A test for the electrostatic model was to reverse the charge ing the frequency of aromatic interactions in proteins, Fersht
distribution in the quadrupole of the aromatic rings. Several et al. measured the magnitude of such an interaction using a
fluorinated compounds were investigated for this purpose double mutant cycle.84 An aromatic pair on the first α-helix
(Fig. 35(b)).81 Progressive fluorination of one phenyl ring of barnase was the interaction of interest. The edge of the
increased the barrier to rotation, due to a decrease in the aromatic ring of Tyrosine 17 (Tyr17) interacts with the face of
mutual repulsion by removal of electron density from the the aromatic ring in Tyrosine 13 (Tyr13) (Fig. 37). In order to
π-systems by the electronegative fluorines. The perfluorinated determine the strength of the interaction, it was necessary to
ring with a reversed quadrupole moment reversed the trend in remove it by mutating one of the residues involved, and then

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Table 7 Edge-to-face aromatic interactions (kJ mol⫺1) in zipper

complexes measured in CDCl3 at 295 K

Substituent X

Substituent Y NO2 H NMe2

NO2 ⫹1.2 ⫺0.2 ⫺1.4

H ⫺3.4 ⫺1.4 ⫺1.1
NMe2 ⫺4.6 ⫺1.8 ⫺0.9
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Fig. 39 The X-ray crystal structure of d(CGCGAAAAAACG) (blue)

with the calculated structure overlaid in red. Only the aromatic bases
Fig. 38 Chemical double mutant cycle to measure the terminal edge- are shown for clarity.
to-face aromatic interaction in complex A. The inset shows the X-ray
crystal structure of a model compound which contains the same inter- were used to construct a chemical double mutant cycle
molecular interaction. (Fig. 38).85 The association constants of all four complexes
were determined by 1H NMR titration and the edge-to-face
measure the difference in stability between the mutated protein interaction for unfunctionalised aromatic rings (X = Y = H)
and wild type. This is useful when the amino acids make no was found to be ⫺1.4 ± 0.8 kJ mol⫺1 in chloroform. An X-ray
other contacts in the protein, but this is generally not true, crystal structure of a model compound was used to probe the
and the analysis of a single mutant is therefore misleading. A geometry of the interaction at the terminus of the zipper and
double mutant cycle allows the isolation of the energetics of confirmed an edge-to-face arrangement of aromatic rings
pairwise interactions between two residues in a protein even (Fig. 38). Substituent effects were investigated by substituting
when they take part in multiple interactions. The two residues the edge and face rings with electron withdrawing and electron
involved in the interaction are replaced by alanine initially as donating groups (Table 7).86 These values correlate with
single mutations, and then as a double mutation (Fig. 37). In Hammett substituent parameters for X and Y (σ), shown in
the first instance, Tyr13 was replaced by alanine (Ala13). The eqn. (2). The last three terms in the equation were interpreted as
change in free energy of unfolding was measured by denatur-
ation using urea. The measurement was then repeated on the ∆∆G (π–π) = 5.2 σXσY ⫺ 1.9 σX ⫹ 1.4 σY ⫺ 1.5 (2)
mutation of Tyr17 to alanine (Ala17). These mutations each
an electrostatic interaction between the positively charged CH
measure the edge-to-face interaction of interest as well as
groups on the edge ring and the negatively charged π-electron
secondary interactions with the surrounding residues. In order
density on the face ring. The first term is attractive when X and
to quantify these secondary interactions, the double mutant
Y have opposite effects which reflects an electrostatic inter-
Ala13, Ala17 is used. Any effects of mutations that do not
action between the overall dipoles caused by the polarising
involve the interaction between the two residues of interest
effects of the substituents.
cancel out in the thermodynamic analysis in Fig. 37. The free
energy for the edge-to-face interaction between Tyr13 and
8 Applications of aromatic interactions
Tyr17 was found to be ⫺5.6 ± 0.3 kJ mol⫺1. The authors con-
clude that an aromatic pair in the hydrophobic core of a protein The knowledge gained from studies of aromatic interactions is
can make a large contribution to the stability of a protein. slowly increasing and the results obtained are being used to
Hunter et al. used a similar approach to measure edge-to-face understand and rationally design new functional molecular
interactions in a synthetic system. H-bonded molecular zippers systems. In order to understand the complex recognition

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Fig. 40 Unsymmetrical rotaxanes and populations at each station.

processes that are associated with DNA, proteins and other thread exhibits a translational equilibrium, with the tetracati-
biological systems, it is important that we understand the onic ring rapidly interchanging between the two stations.90
underlying mechanisms. As aromatic moieties are abundant in However if the thread is unsymmetrical, then the ring exhibits
these biological structures, an understanding of the fund- an affinity for one station over another, due to differences in the
amental interactions between them is vital to further study aromatic interactions (Fig. 40). In rotaxane 1, the ring spends
more complex systems. 50% of its time on each station, with a barrier to shuttling of 54
Hunter et al. have modelled DNA base stacking interactions, kJ mol⫺1. In rotaxane 2, the ring spends 70% of its time on
and the results correlate well with oligonucleotide X-ray crystal station A, because of a stronger stacking interaction with the
structures.87 This approach has been used to parametrise a dialkoxyphenyl ring. In rotaxane 3, the ring prefers to interact
complete model for predicting the sequence-dependent struc- with the benzidine station. Rotaxane 3 can be switched between
ture of DNA. Structures calculated for dodecamers agree with the two conformations chemically or electrochemically.91
X-ray crystal structures to within 1 Å rms difference in the Protonation of the benzidine station with TFA causes electro-
positions of the heavy atoms (Fig. 39). The results explain the static repulsion with the tetracationic ring which moves onto
origins of some fundamentally important properties. For station A. Addition of pyridine reverses this process. Electro-
example, the TATA sequence is the origin of replication, chemical oxidation of the benzidine group leads to charge–
because this is the least stable of all DNA tetranucleotides and charge repulsion and again causes the tetracationic ring to sit
so is relatively easy to open. There are three reasons: TA base over the biphenol station.
pairs have two H-bonds rather than the three found in GC base Stacking interactions play a key role in determining the
pairs; the stacking interactions are weaker than for any other material properties of molecular solids. Perhaps the best
dinucleotide, and the conformational properties of TA and AT studied cases are the semi-conducting charge-transfer com-
steps are incompatible which puts strain on the backbone. Thus plexes based on tetrathiofulvalene and tetracyanoquinone
theoretical models of aromatic stacking interactions are begin- derivatives.92 Semi-conducting properties are obtained provided
ning to contribute to our understanding of complex biological the molecules can be persuaded to form segregated stacks.
processes.88,89 Although there has been little success in engineering the crystal
Stoddart and co-workers have used aromatic stacking packing of such molecules, this is clearly an area of great poten-
interactions to control the behaviour of a molecular shuttle. tial where controlling the aromatic stacking interactions would
A symmetrical rotaxane with multiple donor “stations” on the lead to control over functional properties.

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Fig. 42 (a) Formation of (E)-polybutadiene. (b) Arrangement of

monomers required to yield the (Z) polymer.

Fig. 41 Phenyl–pentafluorophenyl stacking interactions control the

packing of a stilbene derivative in the solid state (a) and hence the
stereochemistry of the cyclobutane photodimer (b).

Coates et al. used stacking interactions in the solid state to

influence the photodimerisation of olefins. In a similar manner Fig. 43 X-Ray crystal structure of 1-(2,3,4,5,6-pentafluorophenyl)-4-
to the way that benzene and hexafluorobenzene form face-to- phenylbutadiyne.
face stacks, (E)-pentafluorostilbene crystallises with long stacks
of alternating phenyl and pentafluorophenyl rings (Fig. 41(a)),
and this leads to a single isomer of the cyclobutane photodimer
(Fig. 41(b)). Dougherty used stacking interactions in the solid
state to align monomeric units for polymerisation.93 A diyne
normally polymerises to give a (E)-polybutadiyne as shown in
Fig. 42(a). If a stacked arrangement of butadiyne units could
be obtained, this should lead to (Z)-polymerisation (Fig. 42(b)).
Diphenylbutadiyne and decafluorodiphenylbutadiyne were co-
crystallised, and the crystal structure revealed the acetylenes
packed alternately in well ordered phenylⴢpentafluorophenyl
stacks. The mixed phenyl–pentafluorophenyl diyne compound Fig. 44 The Sharpless ligand used for the asymmetric dihydroxylation
also crystallises with phenylⴢpentafluorophenyl stacks, so that of olefins.
the molecules sit in a head-to-tail arrangement which appears
ideal for (Z)-polymerisation (Fig. 43). However, no structural
and increasing the size of the aromatic group in both ligand
data on the products of polymerisation reactions have been
and substrate leads to larger rate constants due to favourable
published.
stacking interactions in the binding pocket.
Important aromatic interactions have been found in synthetic
catalytic systems. Sharpless et al. used the ligand in Fig. 44
9 Conclusions
in combination with osmium tetraoxide to influence trans-
ition states in osmium-catalysed asymmetric dihydroxylation The picture that emerges is that aromatic interactions are not
reactions.94 The ligand adopts a U-shaped geometry with the so different from simple interactions like H-bonds: they are
naphthyl groups forming a tweezer-like binding pocket which just complicated by the fact that larger functional groups
sandwiches aromatic substituents on olefins and holds the are involved. The major difference is that the surface area of
double bond in the perfect position to react with the osmium intermolecular contact is large, so van der Waals interactions
tetraoxide. Aromatic substrates react faster than aliphatic ones, and desolvation are much more important. Although the

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electrostatic principles governing the magnitudes of H-bonds 42 S. B. Ferguson and F. Diederich, Angew. Chem., Int. Ed. Engl., 1986,
also apply to aromatic interactions, there are many more con- 25, 1127.
tact points where electrostatic interactions have to be con- 43 D. B. Smithrud and F. Diederich, J. Am. Chem. Soc., 1990, 112, 339.
44 R. E. Sheridan and H. W. Whitlock, J. Am. Chem. Soc., 1988, 110,
sidered, and so it is difficult to rationalise the behaviour of 4071.
aromatic interactions with straightforward rules as in the case 45 B. J. Whitlock and H. W. Whitlock, J. Am. Chem. Soc., 1990, 112,
of H-bonds. Nevertheless, our understanding has progressed to 3910.
the stage where we can produce useful computer models which 46 T. J. Shepodd, M. A. Petti and D. A. Dougherty, J. Am. Chem. Soc.,
describe the properties of aromatic interactions well, and a 1988, 110, 1983.
range of robust aromatic interaction motifs have been 47 A. W. Schwabacher, S. Zhang and W. Davy, J. Am. Chem. Soc.,
1993, 115, 6995.
developed for use in the rational design of new molecular 48 H. J. Schneider, T. Blatter, S. Simova and I. Theis, J. Chem. Soc.,
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