Understanding the regioselectivity in Scholl reactions for the synthesis of oligoarenes

Article abstract of DOI:10.1039/c1cc15980a

A short reaction sequence leads to oligoarene derivatives utilising a regioselective Scholl reaction for the unprecedented cyclisation to the mono-functionalised oligoarene under methanol elimination. Quantum-chemical investigations reveal the reason for the remarkably high regioselectivity.

Full text of DOI:10.1039/c1cc15980a

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COMMUNICATION
Understanding the regioselectivity in Scholl reactions for the synthesis of
oligoarenesw
Michael Danz, Ralf Tonner* and Gerhard Hilt*
Received 26th September 2011, Accepted 1st November 2011
DOI: 10.1039/c1cc15980a
A short reaction sequence leads to oligoarene derivatives utilising
a regioselective Scholl reaction for the unprecedented cyclisation
to the mono-functionalised oligoarene under methanol elimination.
Quantum-chemical investigations reveal the reason for the
remarkably high regioselectivity.
The Scholl reaction is the oxidative cyclisation of suitable
terphenyl and higher open oligoaryl derivatives (such as 3) for
the formation of triphenylenes and other cyclised oligoarene
products (e.g. 4, 5).1 For this purpose a range of oxidizing
agents can be applied successfully and out of many reagents
iron trichloride is the most prominent.2 Recent applications
Scheme 1 Regioselective synthesis of oligoarene 4.
describe the use of hypervalent iodine derivatives introduced by
Kita et al.3 and the combination of MoCl5/TiCl4 introduced
by Waldvogel et al.4 for moderately activated starting materials.
Contemplating the literature it becomes obvious that for the
synthesis of oligoarene derivatives generally symmetrical starting
materials are used.
Inspired by the work of King et al.5 who investigated the
applicability of the Scholl reaction and determining the scope
and limitations of unsymmetrical starting materials, Mullen and
¨
our group independently noticed an unprecedented high selectivity
in a Scholl reaction leading to tribenzo[fg,ij,rst]pentaphene
derivatives such as 4 (Scheme 1).6,7
The synthesis of 3 was accomplished in three steps utilizing a
cobalt-catalysed Diels–Alder reaction of 1 with 2 in the key
step.8 From 3 the Scholl reaction with FeCl3 as oxidizing agent
generates regio-isomer 4 exclusively while the alternative
Scheme 2 Attempted synthesis of oligoarenes of type 7.
regioisomer 5 was not observed.8 Intrigued by Mullen’s statement
¨
‘‘The factors controlling this reaction are still undetermined.’’6
we decided to investigate this selectivity in more detail. For
this purpose, 6a/b were synthesised in order to force the
reaction towards the regioisomers 7 by blocking positions
with alkyl and other functional groups (Scheme 2).
the central arene moiety are non-innocent substituents
while the alkyl chains in the vicinity of the molecule remain
unchanged. The oxidation of this particular central benzene
ring leads to the formation of benzylic radicals initiating side
reactions. This agrees with the electrochemical oxidation of
toluene and multiple methylated benzene derivatives leading
to a variety of products by arene–arene coupling as well
as arene–side chain and side chain–side chain coupling
reactions.10 On the other hand, when the functional group is
a methoxy group (FG = OCH3 in 6), the transformations of
6 with FeCl3 led to 8a (FG = OCH3) as the major product in
74% yield with loss of a methoxy group. Unexpectedly, the
anticipated product of type 7 was not formed. In addition,
when fluorine was chosen as a functional group product
When a methyl or an isopropyl group were selected as
functional groups for blocking coupling sites in 6, the oxidation
with FeCl3 led to the formation of various products.9 This
finding is interesting since it illustrates that the alkyl groups of
Fachbereich Chemie, Hans-Meerwein-Str., 35043 Marburg, Germany.
E-mail: Hilt@chemie.uni-marburg.de, Tonner@chemie.uni-marburg.de;
Fax: +49 6421 2825677; Tel: +49 6421 2825601
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc15980a
8b (FG
=
F) was formed exclusively in 55% yield
c
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Chem. Commun., 2012, 48, 377–379 377

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Scheme 5 Radical cation intermediate 15 for the selective formation
of 4. The dotted lines indicate the positions for carbon–carbon bond
formation.
Scheme 3 Proposed reaction pathway for the formation of 8a by
a Scholl reaction including the elimination of methanol.
(73% based on recovered starting material). Although oxidation of
the fluoro-substituted starting material 6b was significantly slower,
compound 7 could also not be isolated. To exclude that FeCl3 acts
as Lewis acid being responsible for the elimination of methanol,
the reaction with 6a was performed with DDQ (2,3-dichloro-5,
6-dicyanobenzo-quinone) as oxidant. The result was identical to
the reaction with FeCl3 leading to product 8a in 76% yield.
Repeating the reaction with MoCl5/TiCl4 and adopting a
procedure by Waldvogel led to the desired product 8a in 61%.11
The formation of products of type 8 can be rationalized by a
radical cation initiated electrocyclic ring closure (indicated by
the bold highlighted double bonds in 9a, Scheme 3) to generate
intermediates such as 10a which can eliminate methanol (or
HF) for the formation of the detected ring systems (8).12 After
elimination of MeOH from 10a the obtained radical cation
undergoes two more electrocyclic ring closure/oxidation reactions
(in total ꢀ3eꢀ, ꢀ4H+) for the synthesis of 8a.
Scheme 6 Possible reaction pathways toward 8a. The dotted lines
indicate the positions for carbon–carbon bond formation.
is determined in the second step of the reaction and not in the
first cyclisation step (Scheme 5).
In this case the reaction pathway c is exclusively chosen over
pathway d in the proposed intermediate 15 leading to product
4. In the cases of the functionalised starting materials 6a and
6b two different scenarios have to be taken into account
(Scheme 6).
The control experiments outlined in Scheme 4 revealed that
intermediate 16 is not formed so that the two reaction pathways
e and f can be ignored. Intermediate 17 is formed by the ‘‘non-
classical’’ cyclisation under Scholl conditions. From there,
only pathway g is chosen for the formation of product 8a
over pathway h, which would lead to a doubly demethoxylated
product, which is not observed.
At this point it was not clear whether the electrocyclic
reaction involving the methoxy position took place during
the first ring closure process or if the second electrocyclic ring
closure incorporates the step to eliminate methanol.
For this purpose test system 11 (Scheme 4) was synthesized
where the Scholl reaction led to two products. Following pathway
b product 14 was isolated in 8% yield via 12 while the major
product 140 was formed by dimerization of 12 in 51% yield.
Utilising DDQ12–14 as oxidant the dimer 140 was isolated in 39%
yield accompanied with 20% of recovered starting material,
whereas 14 was formed in very low yield (o5%).15
Quantum-chemical calculations at the DFT level (B3LYP/
def2-TZVPP//LC-oPBE/def2-SVP) were undertaken to
explain the observed regioselectivity. The starting points for
the calculations were the radical cations of 15 and 17 (with
hexyl-groups substituted by methyl-groups) which have been
termed AX with X = H, F, OMe (see Fig. 1). Since the
biphenyl-moiety was found to exhibit only a small difference
between rotamers (DE o 5 kcal molꢀ1) of the C–C bond to the
central ring, the conformation of AX is not relevant.
Transition structures and intermediates were located
for both possible pathways proposed in Schemes 5 and 6.16
The relative energies of the transition states indicate that the
The alternative product 13 which is possibly formed via
pathway a was not detected. The results indicate that the
reaction via pathway b is strongly favoured over reaction
pathway a when FeCl3 or DDQ were used as oxidant.
For the first system described herein, the Scholl reaction of 3
and the regioselective formation of 4, these results are rather
irrelevant because the regioselectivity for the product formation
Fig. 1 Free energies DG(LC-oPBE/def2-SVP) for the selectivity-
determining transition states relative to AX (X = H, F, OMe (underlined
values); R = Me).
Scheme 4 System 11 for testing the site-specific Scholl reaction. The
dotted lines indicate the positions for carbon–carbon bond formation.
c
378 Chem. Commun., 2012, 48, 377–379
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Table 1 Energy differences (kcal molꢀ1), bond lengths for the newly
formed bond (A) and transition state frequencies (cmꢀ1) for the crucial
transition states shown in Fig. 2
In conclusion, we presented a comprehensive explanation
for the highly regioselective Scholl reaction leading to the
formation of tribenzo[fg,ij,rst]pentaphene derivatives by joint
experimental and quantum chemical investigations. Also, the
successful isolation of unprecedented mono-functionalised
tribenzo-[fg,ij,rst]pentaphene derivatives will be useful to eval-
uate future syntheses of oligoarene and graphene materials via
a Scholl reaction for unsymmetrical starting materials in the
synthesis of complex polyarene architectures.
TSA-B1X
TSA-B2X
r(C–C) nTS
r(C–C) nTS
X
DEa,b DEa,c DGa,b
H
F
2.8
4.8
0.7
2.6
5.3
2.0
4.2
5.3
1.781
1.729
1.775
ꢀ495 1.798
ꢀ589
ꢀ497 1.772
ꢀ531
OMe 6.1
ꢀ488 1.771
ꢀ523
E/G(TSA-B2X).
a
(Free) energy difference: E/G(TSA-B1X)
c
LC-oPBE/def2-SVP. B3LYP/def2-TZVPP//LC-oPBE/def2-SVP.
ꢀ
b
Notes and references
1 R. Scholl and J. Mansfeld, Ber. Dtsch. Chem. Ges., 1910, 43, 1734;
P. Kovacic and M. B. Jones, Chem. Rev., 1987, 87, 357.
barriers towards the experimentally observed product D1X (via
radical cation C1X) are favoured for all substituents X.
The free energy differences G(TSA-B1X) ꢀ G(TSA-B2X)
are 2.0 kcal molꢀ1 (X = H), 4.2 kcal molꢀ1 (X = F) and
5.3 kcal molꢀ1 (X = OMe) which are in line with the
experimentally observed high regioselectivity of the Scholl
reaction. Note that the calculated transition states exhibit
antarafacial arrangements of the aromatic rings. An alternative
suprafacial arrangement possesses transition states which are
5–10 kcal molꢀ1 higher in energy. Therefore, they are not
further discussed (details can be found in the ESIw).
The calculations indicate that the transition states lead to
energetically high lying intermediates B1X and B2X for all
substituents. We conclude that the intermediates are instanta-
neously deprotonated by chloride anions which are available
in solution forming HCl. Indeed, HCl has been experimentally
observed, confirming this assumption. The final product
regioisomer D1X is then formed via radical cation C1X in a
third electrocyclic reaction, in accordance with the experiment.
The energy differences for the crucial transition states are
consistent for both density functionals applied and range
between 0.8 and 6.1 kcal molꢀ1 (Table 1). The same holds
true for the difference in free energies. Thus for all substituents
a clear kinetic preference for the experimentally observed
pathway is found.
2 M. Klussmann and D. Sureshkumar, Synthesis, 2011, 353; A. A.
O. Sarhan and C. Bolm, Chem. Soc. Rev., 2009, 38, 2730.
3 For selected reviews, see: T. Dohi, M. Ito, N. Yamaoka,
K. Morimoto, H. Fujioka and Y. Kita, Tetrahedron, 2009,
65, 10797; H. Tohma, H. Morioka, S. Takizawa, M. Arisawa
and Y. Kita, Tetrahedron, 2001, 57, 345.
4 N. M. Boshta, M. Bomkamp, G. Schnakenburg and S. R. Waldvogel,
Eur. J. Org. Chem., 2011, 1985; N. M. Boshta, M. Bomkamp,
G. Schnakenburg and S. R. Waldvogel, Chem.–Eur. J., 2010,
16, 3459; N. M. Boshta, M. Bomkamp and S. R. Waldvogel,
Tetrahedron, 2009, 65, 3773; A. Spurg, G. Schnakenburg and
S. R. Waldvogel, Chem.–Eur. J., 2009, 15, 13313.
5 J. L. Ormsby, T. D. Black, C. L. Hilton, Bharat and B. T. King,
Tetrahedron, 2008, 64, 11370; B. T. King, J. Kroulık,
´
C. R. Robertson, P. Rempala, C. I. Hilton, J. D. Korinek and
L. M. Gortari, J. Org. Chem., 2007, 72, 2279; P. Rempala,
J. Kroulık and B. T. King, J. Org. Chem., 2006, 71, 5067.
´
6 L. Dossel, L. Gherghel, X. Feng and K. Mullen, Angew. Chem.,
¨
Int. Ed., 2011, 50, 2540.
¨
7 M. Danz and G. Hilt, Adv. Synth. Catal., 2011, 353, 303.
8 A.-L. Auvinet, J. P. A. Harrity and G. Hilt, J. Org. Chem., 2010,
75, 3893; G. Hilt and J. Janikowski, Org. Lett., 2009, 11, 773;
P. Morschel, J. Janikowski, G. Hilt and G. Frenking, J. Am. Chem.
¨
Soc., 2008, 130, 8952; G. Hilt and M. Danz, Synthesis, 2008, 2257;
G. Hilt and C. Hengst, J. Org. Chem., 2007, 72, 7337; G. Hilt and
C. Hengst, Synlett, 2006, 3247; G. Hilt, J. Janikowski and W. Hess,
Angew. Chem., Int. Ed., 2006, 45, 5204.
9 In the case of FG=CH3 the methyl groups disappear and in
1H NMR olefinic protons can be detected.
10 O. Hammerich, in Organic Electrochemistry, ed. H. Lund and
O. Hammerich, Dekker, New York, 2001, ch. 13, p. 471.
11 When AlCl3 or MeSO3H was applied in the absence of an oxidizing
agent no conversion was observed.
In the analysis of the crucial transition states we found that
the preference for the pathway via TSA-B1X can be understood
in terms of frontier orbital analysis. Fig. 2 shows the LUMO of
12 L. Zhai, R. Shukla, S. H. Wadumethrige and R. Rathore, J. Org.
Chem., 2010, 75, 4748; O. Hammerich and V. D. Parker, Adv.
Phys. Org. Chem., 1984, 20, 55; E. Haselbach, T. Bally and
Z. Lanyiova, Helv. Chim. Acta, 1979, 62, 577.
AH and AF (AOMe looks similar). Upon inspection of the orbital
coefficients it can be seen that the coefficients at the central
aromatic ring are distributed unevenly. For all substitution
patterns, the carbon atoms being attacked through pathway c
(Scheme 5, AH) or g (Scheme 6, AF) exhibit the larger orbital
coefficients.
13 P. J. Donoghue and O. Wiest, Chem.–Eur. J., 2006, 12, 7019.
14 L. Zhai, R. Shukla and R. Rathore, Org. Lett., 2009, 11, 3474;
T. S. Navale, K. Thakur and R. Rathore, Org. Lett., 2011, 13, 1634.
15 The product was accompanied by an unidentified side-product.
16 Note that the transition states TSA-B1X could only be located with
the functional LC-oPBE. Previous attempts with B3LYP, BP86,
M06-2X, B97D and TPSS failed to locate a stationary point. The
observation that the identification of intermediates depends on the
method employed in radical cation reactions has been found earlier
(see ref. 13). Extensive benchmark studies on present day density
functionals (L. Goerigk and S. Grimme, Phys. Chem. Chem. Phys.,
2011, 13, 6670) reveal that care has to be taken in choosing the right
functional and basis set for studies in organic chemistry similar to
more challenging transition-metal catalyzed reactions. Although for
pericyclic reactions B3LYP has been found to provide reasonably
accurate results (T. Schwabe and S. Grimme, Acc. Chem. Res., 2008,
41, 569) excellent agreement with higher level calculations has been
found for radical cation reactions. (U. Haberl, O. Wiest and
E. Steckhan, J. Am. Chem. Soc., 1999, 121, 6730.) For further
details see the ESI.w In accordance with earlier observations (ref. 13
and therein), a non-aromatic to slightly antiaromatic character of
the transition states has been found by NICS computations.
It follows that the observed reactivity pattern is in line with
an orbital controlled reaction which may be used as an easy
probe for future studies on regioselective Scholl reactions.
Fig. 2 Lowest unoccupied orbital (LUMO) for AH (left) and AF
(right) with orbital energies (B3LYP/def2-TZVPP).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 377–379 379