Tetrahedron Letters 55 (2014) 2078–2081
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Aromaticity of caffeine, xanthine and the dimethyl xanthines
http://dx.doi.org/10.1016/j.tetlet.2014.02.0270040-4039/� 2014
Elsevier Ltd. All rights reserved.
⇑ Corresponding author.E-mail address:
[email protected] (P.W. Fowler).
Figure 1. Schematic structures of the aromatic molecules treated
in thxanthine (1), caffeine (2), paraxanthine (3), theobromine (4)
and theophyAlso considered are imidazole (6), corresponding to
heavy atoms 4, 5, 7, 8 amethylimidazole (7), corresponding to R0 =
Me on atom 7.
Christopher M. Gibson, Patrick W. Fowler ⇑Department of
Chemistry, University of Sheffield, Sheffield S3 7HF, UK
a r t i c l e i n f o a b s t r a c t
Article history:Received 14 October 2013Revised 28 January
2014Accepted 12 February 2014Available online 20 February 2014
Keywords:AromaticityRing currentCaffeineXanthine
Xanthine, caffeine and three isomeric dimethyl xanthines
(theobromine, theophylline and paraxanthine)are often described as
aromatic on various criteria. Here we complete the picture by
assessing these mol-ecules for aromaticity on the ring-current
criterion. Magnetic response calculations are performed at theB3LYP
and CHF/6-31G⁄⁄ ipsocentric levels of theory on structures
optimised at the B3LYP/6-31G⁄⁄ level.All five systems display
consistent p-electron ring-currents delocalised around the
imidazole moiety inall cases; these are accompanied by localised
features on the six-membered rings attributed to nitrogenand oxygen
‘lone-pair’ p-electron circulations. All are therefore aromatic on
the magnetic criterion, with a‘locally delocalised’ ring current in
the imidazole moiety, similar to those in the isolated imidazole
andmethylimidazole molecules.
� 2014 Elsevier Ltd. All rights reserved.
The methylated derivatives of xanthine (1) [i.e., caffeine
(2),paraxanthine (3), theobromine (4) and theophylline (5)] (Fig.
1)are all mild stimulants and are widely consumed via sources
suchas tea, coffee and chocolate. Their bioactive properties are
manyand varied. Caffeine, first isolated in 1819 by Ferdinand Runge
aftera gift of Arabian mocha coffee beans from Johann Wolfgang
vonGoethe,1,2 has recently been linked to Parkinson’s disease as
botha preventative measure and a palliative treatment.3–7
The claimed neuroprotective effect has been attributed to
bind-ing to adenosine A2A receptors.3,7–9 Paraxanthine, theobromine
andtheophylline are the primary metabolites of caffeine.10 All
three, toa greater or lesser extent, share the propensity of their
parent mol-ecule to act as an inhibitor of A2A receptors,8,11–13
show therapeuticuses as stimulants of the central nervous
system,11,12 and exhibitdiuretic properties.13
The aromaticity of these 14p structures has been
discussedextensively,14,15 and we may note the planarity of the
heavy-atomframework and the participation of these molecules in
p-stackinginteractions as corroborative factors. A widely accepted
definitionof aromaticity is based on the magnetic response of the p
electronsin these systems. On the magnetic criterion of
aromaticity, an aro-matic/anti-aromatic system is one that supports
a diatropic/para-tropic ring current when subjected to a
perpendicular externalmagnetic field. Ring current models have been
invoked in discus-sions of intermolecular interactions of
caffeine,16 and 1H NMR datafor the molecules 1–5 are consistent
with the existence of a ringcurrent in, at least, the imidazole
portions of these molecules.15–17
If indeed the xanthines are aromatic, it should be possible to
calcu-late and to visualise the ring currents using quantum
chemicaltechniques, and hence confirm their aromaticity on the
magneticcriterion. This is the aim of the present study.
Method
It is now possible to calculate and map magnetic-field
inducedcurrent density in molecular systems, thereby explicitly
testing forthe presence of the ring currents associated with
aromaticity. Amethodology which has become a standard for such
calculationsinvolves the application of the ipsocentric approach.18
In ipsocen-tric calculations the previously intractable problem of
gauge-dependence of computed results is sidestepped by choosing
theorigin for calculation of current density at any point to be the
pointitself. This simple idea, originally due to Keith and Bader,19
hasbeen shown to give physically realistic patterns of current for
psystems with modest basis sets and at moderate computational
is study:lline (5).nd 9, and
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C. M. Gibson, P. W. Fowler / Tetrahedron Letters 55 (2014)
2078–2081 2079
cost. It has the unique feature20 that the calculated current
densitycan be partitioned into non-redundant orbital contributions,
lead-ing to an interpretative scheme and hence a ‘frontier-orbital
the-ory’ of aromaticity.18,21 The counterpart of the simple
Hückel4n+2/4n electron counting for delocalised p cycles is a more
widelyapplicable statement based on the symmetry of the
HOMO–LUMOtransition:21 when this transition from an occupied to an
emptyorbital would increase the number of angular nodes by one,
thesystem will have a 4-electron diatropic (aromatic) current;
whenthe transition would preserve the number of angular nodes,
thesystem will support a two-electron paratropic
(anti-aromatic)current.
In order to carry out calculations with this approach, the
struc-tures [1–5 and, for comparison, imidazole itself (6) and
1-methyl-imidazole (7)] were first optimised in Cs symmetry, and
confirmedas energetic minima on the potential energy surface at the
B3LYP/6-31G⁄⁄ level with Gaussian 09.22 The calculated geometries
agreewell with previous experimental and theoretical studies.23–27
Forthese structures, magnetic response was calculated at the
coupledHartree-Fock level in the 6-31G⁄⁄ basis set with the
ipsocentric18
choice of origin for the current and using the SYSMO28
package.We are particularly interested here in the response of the
p
electrons. The ipsocentric method allows partition of total
proper-ties into contributions from individual orbitals. All such
decompo-sitions are arbitrary to some degree as no recombination
ofoccupied orbitals amongst themselves can change total
energy,charge density or current density. The usual choice lies
betweenthe maximally delocalised canonical molecular orbitals
(CMOs)and maximally localised molecular orbitals (LMOs) obtained
by,for example, the Pipek–Mezey29 method. Differences in
intrinsiclocalisation of the p electrons in different systems are
reflectedby the ipsocentric orbital contributions obtained with
these twosets. A fully delocalised ring current such as that in
benzene is eco-nomically described by the CMO set, where p ring
current arisesalmost entirely from the HOMO;30 in a localised
system such asborazine the p current is a sum of lone pair
circulations, each aris-ing from a single LMO. In the present
system we expect to find a
Figure 2. Total p current–density maps for systems 1–7. Maps are
constructed by summlone pair and carbonyl circulations (1–5), plus
those of 3 LMOs corresponding to the p sysand plotting plane are
described in the text.
mixture of global and local currents and the comparison of
CMOand LMO contributions should be especially instructive.
Currents were therefore analysed both in terms of
contributionsfrom CMOs and from Pipek–Mezey LMOs. In these planar
systems,the CMOs are of A0 and A00 symmetries. All r orbitals are
A0, and allp orbitals are A00, but some (one per Me group) A00
orbitals corre-spond simply to out-of-phase combinations of CH
bonds and soare not part of the unsaturated p system. These
orbitals are easilyidentified and discounted in the discussion of p
ring current. Thesystems 1 to 5 thus all have 7 CMOs in the p
space. In the localisedtreatment, 7p LMOs are obtained immediately
on removal of coresand r bonds.
Current–density maps, plotted at a distance of 1 a0 above
themean plane of the heavy nuclei, illustrate the first-order
magneticresponse of the p system induced by an applied
perpendicularmagnetic field. Aromaticity (anti-aromaticity) is
diagnosed in thesemaps by the presence of anticlockwise (clockwise)
loops of current.
In the maps, contours and shading reflect the modulus of the
in-duced current density per unit external field. Arrows indicate
thecomponent of current–density resolved into the plotting
plane,with diatropic/paratropic currents diagnosed by
anticlockwise/clockwise circulations. Carbon atoms are represented
by filledblack circles surrounded by a white border, hydrogen by
dottedwhite circles, nitrogen by divided white circles and oxygen
by filledblack circles.
Calculations of the induced currents at the B3LYP/6-31G⁄⁄
levelwere also performed with a combination of the
GAMESS-UK31,32
and SYSMO packages. The resultant maps for these DFT
calcula-tions are not shown, as there was no significant variation
fromthe maps of induced current density calculated using
HF-basedmethods.
Results and discussion
The total p current–density maps for structures 1–7 are shownin
Figure 2. To a first approximation, all five
xanthine-derivedsystems display the same ring-current pattern:
strong, coherent
ation of the contributions of 4 LMOs corresponding to the
contributions of nitrogentem of the imidazole moiety (1–7).
Plotting conventions in terms of contours, arrows
Figure 3. LMO analysis of the p-current in caffeine (2), showing
(a) the three LMO contributions to the imidazole ring, (b) the two
nitrogen lone pairs and the carbonyl oxygenp circulations that
contribute the remainder of the total p current.
2080 C. M. Gibson, P. W. Fowler / Tetrahedron Letters 55 (2014)
2078–2081
diatropic circulation around the imidazole unit consistent
withthat in imidazole itself (6), with weaker, localised
circulations posi-tioned on the nitrogen and oxygen centres in the
rest of the sys-tem. The imidazole-based circulations in 1–7 can be
shown byLMO analysis to be genuinely delocalised features (see Fig.
3); theycan each be constructed in their entirety by
superimposition ofcontributions from 3p LMOs, none of which by
itself gives a closedcirculation.20,33 This imidazole current is
delocalised, but over aconfined region of the molecular skeleton.
Such behaviour hasbeen dubbed ‘locally delocalised’ in studies of
benzenoid–borazi-noid34 and graphene/graphane hybrids.
To give a more quantitative measure of the current strength,
themaximum value of the modulus of the current–density in the
plot-ting plane (jmax) can be used. This indicator also lends
itself to acomparison with the benzene ‘standard’ calculated with
the samemethod in the same basis. The benzene p current at a height
of 1 a0above the molecular plane has jmax = 0.080 and 0.079 a.u.,
respec-tively, for ipsocentric CHF and DFT (B3LYP) calculations in
this ba-sis. Table 1 reports jmax values for the p system in each
moleculecalculated at the two levels of theory. The agreement
betweenCHF and DFT is, as expected,35 excellent.
Examination of Table 1 brings to light some second order
differ-ences in the strengths of the induced current that were not
imme-diately evident from inspection of the maps. In particular,
thecurrents in the delocalised rings of caffeine, paraxanthine
andtheobromine (jmax = 0.079–0.080 a.u.) are noticeably stronger
thanthose in xanthine and theophylline (jmax = 0.070–0.071
a.u.).
The primary structural differences between these systems
arisefrom the presence of methyl groups on the imidazole units of
2, 3
Table 1Total p current–density jmax values (a.u.) for the seven
studied structures
Total p current (CHF) Total p current (DFT)
Xanthine 0.071 0.070Caffeine 0.080 0.079Paraxanthine 0.080
0.079Theobromine 0.079 0.079Theophylline 0.070 0.070Imidazole 0.077
0.077Methylimidazole 0.087 0.088
and 4. This suggests that the differences in magnetic response
maybe attributable to the r-inductive effect of the methyl
groups.Comparison of the induced p currents of imidazole (6)(jmax =
0.077 a.u.), and 1-methylimidazole (7) (functionalised inthe same
position, jmax = 0.087 a.u.), leads to the same conclusion;the
presence of a methyl group at this site increases noticeably
thestrength of the p current circulation.
The same trend is found for imidazole itself, where
methylationat the site corresponding to N7 leads to an increase of
�0.010 a.u.in jmax. A crude point-charge model suggests that the
direction ofthis change is attributable to the r-inductive effect
of the methylgroup: if nuclear charge is formally transferred from
H to N in unitsof 0.1 e, the calculated jmax increases, although by
only �0.001 a.u.for each step.
In conclusion, magnetic response calculations of xanthine,
caf-feine, paraxanthine, theobromine and theophylline at the CHFand
DFT B3LYP/6-31G⁄⁄ ipsocentric levels of theory have revealedstrong,
delocalised p ring-currents around their imidazole sub-units. The
total p-response of each molecule can be built up byconsidering the
delocalised ring and localised group contributionsseparately, in a
way that may be useful for more complex systems.Small differences
in current strength between the systems thathave N-hydrogen
(xanthine and theophylline) or N-methyl(caffeine, paraxanthine and
theobromine) on N-7 appear to beconsistent with the r-inductive
effect of the alkyl group.
Acknowledgments
C.M.G. thanks the University of Sheffield for a Ph.D.
studentship.P.W.F. thanks the Royal Society/Leverhulme Trust for a
SeniorResearch Fellowship. Charlotte Mable (University of
Sheffield) isthanked for making a helpful critical survey of the
literature.
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Aromaticity of caffeine, xanthine and the dimethyl
xanthinesMethodResults and discussionAcknowledgmentsReferences and
notes
