Molecular structures of the photodimers of 5-phenyluracil and 6-phenyluracil

Article abstract of DOI:10.1016/j.tetlet.2013.03.026

Two new head-to-head cyclobutane photodimers have been obtained in single stereoisomeric form by irradiation of 5-phenyl- and 6-phenyluracils in acetone solution. While the latter substrate gives a cis-anti-cis adduct, the former provides, for the first time in a solution phase reaction, a cis-syn-cis photodimer as the only product.

Full text of DOI:10.1016/j.tetlet.2013.03.026

Tetrahedron Letters 54 (2013) 2536–2537
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Molecular structures of the photodimers of 5-phenyluracil and 6-phenyluracil
Anne Vidal a, Renée Paugam a, Régis Guillot a, Sophie Faure b, Elisabeth Pereira b, David J. Aitken a,
⇑
a Université Paris-Sud, ICMMO—CNRS UMR 8182, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France
b Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP10448, F-63000 Clermont-Ferrand, and CNRS, UMR 6296, ICCF, BP 80026,
F-63171 Aubière, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new head-to-head cyclobutane photodimers have been obtained in single stereoisomeric form by
irradiation of 5-phenyl- and 6-phenyluracils in acetone solution. While the latter substrate gives a
cis–anti–cis adduct, the former provides, for the first time in a solution phase reaction, a cis–syn–cis
photodimer as the only product.
Received 8 February 2013
Revised 5 March 2013
Accepted 6 March 2013
Available online 15 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclobutane
Photochemistry
Pyrimidinedione
X-ray diffraction
The photodimerization reactions of pyrimidinediones to give
substituted cyclobutanes have been of interest for some time,
notably due to the detrimental effects these processes can have
on DNA.1 The solution phase photodimerization reactions of uracil
and thymine often lack selectivity. Uracil itself is known to give
four isomers — the cis–syn–cis and cis–anti–cis stereoisomers of
each of the head-to-head (HH) and head-to-tail (HT) regioisomers
— in proportions which depend on the conditions applied and are
not easy to control.2 Various approaches have been considered in
attempts to improve selectivity, including the use of temporary
tether3 or recognition-directed supramolecular assistance.4 This
latter approach serves as a reminder that cis–syn–cis pyrimidinedi-
one cyclobutane dimers have been considered as rigid templates
for two-site molecular recognition5 and as model substrates for
mimetics of DNA photolyase activity.6 Such applications remain
somewhat underdeveloped, perhaps due to the difficulties encoun-
tered in the selective synthesis of such dimers. Indeed, surprisingly
few C-substituted pyrimidinedione photodimers have been
prepared and characterized. In solution, the acetone-sensitized
photodimerization of 6-methyluracil gave a mixture of a HH and
HT regioisomers, each with a cis–anti–cis configuration.7 Under
similar conditions, 5-fluorouracil photodimerization provided
predominantly the HT cis–anti–cis adduct.8 The same regio- and
stereochemical profile was observed for the solution-state
photodimers of orotic acid and of its methyl ester.9
5-phenyluracil (1) and 6-phenyluracil (2) had a propensity to form
self-condensation products, presumed to be photodimers.10 Here-
in, we present the unambiguous preparation of these dimers and
their molecular structures.
Irradiation of an acetone solution of 1 or 2 (400 W Hg vapor
lamp, Pyrex filter, 6 h) provided, after simple work up, photodi-
mers 3 and 4 as white powders in good isolated yields (65% and
74%, respectively) (Fig. 1). The observation of only one set of signals
in the 1H and 13C NMR spectra indicated that a single isomer had
been obtained in each case.11 However, in order to establish the
structure, X-ray analysis was necessary. Single crystals were grown
by slow evaporation of a solution in a polar aprotic solvent (DMSO
for 3, DMF for 4) and diffraction studies revealed that the 5-phenyl-
uracil dimer 3 had a HH cis–syn–cis structure, while the 6-phenyl-
uracil dimer 4 had a HH cis–anti–cis geometry (Fig. 2).12
Compound 3 is the first cis–syn–cis uracil photodimer to be
obtained as a unique photoadduct without recourse to elaborate
structural constraints (intramolecular tethers) or medium effects
(frozen matrix, thin film solid state reactions) during the
photoreaction, or painstaking separation of photodimer
O
O
O
O
Ph Ph
H
H
HN
NH
HN
NH
During
a study of the photochemical [2+2] cycloaddition
O
N
H
N
H
O
O
N
H
N
H
O
reactions of pyrimidinediones with ethylene, we discovered that
H
H
Ph Ph
4
3
⇑
Corresponding author. Tel.: +33 1 6915 3238; fax: +33 1 6915 6278.
E-mail address: david.aitken@u-psud.fr (D.J. Aitken).
Figure 1. Molecular structures of photodimers 3 and 4.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.026

A. Vidal et al. / Tetrahedron Letters 54 (2013) 2536–2537
2537
Table 1
Calculated energies of different steps in the photodimerization of 5-phenyluracil (1)
and 6-phenyluracil (2)a
Substrate
1
Geometry
Transition stateb
Biradicalb (T1)
Product
syn
anti
ꢀ4985.53
ꢀ4985.48
0.05
ꢀ5009.91
ꢀ5008.48
1.43
ꢀ5012.61
ꢀ5019.84
7.23
D
E
2
syn
anti
ꢀ4991.53
ꢀ4991.65
0.12
ꢀ5024.53
ꢀ5023.83
0.70
ꢀ5022.08
ꢀ5028.32
6.24
D
E
a
Total energy is given in kcal molꢀ1. The lower energy at each step is in bold.
The value given is for the most energetically stable approach (transition state)
b
or conformer (biradical).
Figure 2. ORTEP plots (30% probability) of the X-ray structures of the photodimers,
showing the HH cis–syn–cis configuration of (left) and the HH cis–anti–cis
configuration of 4 (right). Solvent molecules have been removed for clarity.
3
the origins of the stereoselectivity may lie in self-association
effects in the solution, via some kind of stacking phenomenon;
such an effect was previously suggested to operate in the photodi-
merization of tetramethyluracil.15
In summary, we have prepared and characterized two new
pyrimidinedione photodimers. The molecular structure of one of
these, compound 3, is of particular interest being the most-easily
synthesized cis–syn–cis adduct to date and offering a multiple
hydrogen bond donor/acceptor functional group montage. Since
the pendant aryl groups may act as chromophores and points of
attachment to larger scaffolds, this system may inspire new inves-
tigations of cyclobutane photodimers as templates for molecular
recognition.
References and notes
Figure 3. Views of the cis–syn–cis structure of compound 3 from above (left) and
side-on (right), highlighting the orientation of the heterocyclic systems. Phenyl
rings are removed for clarity.
1. Cadet, J.; Vigny, P. In The Photochemistry of Nucleic Acids; Morrison, H., Ed.;
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mixtures.13 The puckered cyclobutane has a mean torsion angle of
21° and the heterocycles are flattened half-chairs, twisted by about
30° from superposition (Fig. 3, left). This makes for a closer align-
0
ment of the hydrogen-bond donor–acceptor pairs N1–H/C2 @O,
0
0
/C2@O N3 –H, and N3–H/C4 @O of neighboring heterocycles
(Fig. 3, right).
The photosensitizing effect of acetone implicates the triplet
excited state of 1 or 2, and formation of the first bond should occur
between the non-arylated positions to provide a stabilized biradi-
cal intermediate, leading to a HH regioisomer in each case. How-
ever it was not clear why one adduct should be anti while the
other was syn. We performed semi-empirical calculations to verify
the feasibility of formation of the observed structures.14 For each
substrate 1 and 2 the transition state (TS), biradical intermediate
and dimer product energies for both syn and anti structures were
determined (Table 1). For 1, virtually no difference was apparent
between the TS energies of the syn and anti approaches, although
the syn biradical was 1.43 kcal molꢀ1 more stable. While the anti
product is more stable than the syn, there is no energy barrier to
the formation of the latter. For 2, even less difference was evident
between the energies of the syn and anti biradicals, with syn being
favored by only 0.70 kcal molꢀ1 and the anti TS being marginally
more favorable. Here again, there is no clear-cut argument in favor
of either approach mode; the only significant energy difference is
the greater stability of the anti dimer product. It thus appears that
a reaction pathway to either syn or anti geometry is available, so
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9. (a) Birnbaum, G. I. Acta Crystallogr., B. 1972, 28, 1248–1254; (b) Birnbaum, G. I.;
Dunston, J. M.; Szabo, A. G. Tetrahedron Lett. 1971, 947–950.
10. Gauzy, C.; Saby, B.; Pereira, E.; Faure, S.; Aitken, D. J. Synlett 2006, 1394–1398.
11. Compound 3: White solid, mp >360 °C (DMSO). 1H NMR (300 MHz DMSO-d6) d
4.39 (2H, s), 7.21 (10H, m), 7.99 (2H, s), 10.27 (2H, s). 13C NMR (75 MHz DMSO-
d6) d 58.2, 54.5, 127.5, 127.8, 128.0, 135.8, 152.4, 169.4. Compound 4: White
solid, mp 279 °C (DMF). 1H NMR (300 MHz DMSO-d6) d 4.19 (2H, s), 7.407.50
(10H, m), 7.87 (2H, s), 10.48 (2H, s). 13C NMR (75 MHz DMSO-d6) d 39.1, 64.8,
127.0, 128.0, 128.4, 137.4, 151.5, 167.7.
12. CCDC 916146 and CCDC 916145 contain the crystallographic data for
compounds 3 and 4, respectively. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
13. The cis–syn–cis uracil photodimer has been characterized: see (a) Adman, E.;
Gordon, M. P.; Jensen, L. H. Chem. Commun. 1968, 1019–1020; (b) Adman, E.;
Jensen, L. H. Acta Crystallogr., B. 1970, 26, 1326–1334.
14. Semi-empirical calculations were performed with Hyperchem 5.1 using the
PM3 method with the Unrestricted Hartree-Fock wave function. The Polak-
Ribiere algorithm with conjugate gradient calculations was adopted for
geometry optimizations. For the dimerization process, one molecule was
considered in the first excited triplet state, and the other was considered in the
singlet ground state. Transition states were searched by quadratic synchronous
transit algorithm. Radical intermediates were treated in the first triplet state.
15. Otten, J. G.; Yeh, C. S.; Byrn, S.; Morrison, H. J. Am. Chem. Soc. 1977, 99, 6353–
6359.