Revisiting Kekulene: Synthesis and Single-Molecule Imaging

Article abstract of DOI:10.1021/jacs.9b07926

Four decades after the first (and only) reported synthesis of kekulene, this emblematic cycloarene has been obtained again through an improved route involving the construction of a key synthetic intermediate, 5,6,8,9-tetrahydrobenzo[m]tetraphene, by means of a double Diels-Alder reaction between styrene and a versatile benzodiyne synthon. Ultra-high-resolution AFM imaging of single molecules of kekulene and computational calculations provide additional support for a molecular structure with a significant degree of bond localization in accordance with the resonance structure predicted by the Clar model.

Full text of DOI:10.1021/jacs.9b07926

Subscriber access provided by Columbia University Libraries
Communication
Revisiting Kekulene: Synthesis and Single Molecule Imaging
Iago Pozo, Zsolt Majzik, Niko Pavli#ek, Manuel Melle-Franco,
Enrique Guitián, Diego Peña, Leo Gross, and Dolores Pérez
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07926 • Publication Date (Web): 17 Sep 2019
Downloaded from pubs.acs.org on September 17, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Revisiting Kekulene: Synthesis and Single Molecule Imaging
Iago Pozo†, Zsolt Majzik‡, Niko Pavliček‡, Manuel Melle-Franco§, Enrique Guitián†, Diego Peña*†, Leo
Gross‡ and Dolores Pérez*.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
† Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química
Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela (Spain)
‡ IBM Research – Zürich. 8803 Rüschlikon (Switzerland)
§
CICECO, Aveiro Institute of Materials, Department of Chemistry. University of Aveiro. 3810-193 Aveiro (Portugal)
Supporting Information Placeholder
19781,8 is considered to be a landmark achievement in
the field of aromatic chemistry. Only two additional
ABSTRACT: Four decades after the first (and only)
reported synthesis of kekulene, this emblematic
cycloarene has been obtained again through an improved
route involving the construction of a key synthetic
intermediate, 5,6,8,9-tetrahydrobenzo[m]tetraphene, by
means of a double Diels-Alder reaction between styrene
and a versatile benzodiyne synthon. Ultrahigh resolution
AFM imaging of single molecules of kekulene and
computational calculations provide additional support
for a molecular structure with a significant degree of
bond localization in accordance with the resonance
structure predicted by Clar model.
nearly
planar,
unsubstituted
cycloarenes,
and
cyclo[d,e,d,e,e,d,e,d,e,e]deka-kisbenzene9
septulene10 have been synthetized so far, while
substituted analogues of kekulene and of the higher
homologue, non-planar, octulene have been recently
accessed taking advantage of their higher solubility.11
However, the Staab & Diederich’s synthesis of the
parent kekulene (Scheme 1) remains unsurpassed, and
apparently unrepeated, since the only available
experimental studies on 1 are those reported by this
group forty years ago.1,8,12
Cycloarenes1 constitute a fascinating class of polycyclic
aromatic hydrocarbons (PAHs) that have attracted the
scientific community for decades due to the singularity
of their molecular and electronic structures.2 They serve
as ideal platforms to investigate fundamental questions
around the concept of aromaticity and, in particular,
those related with the π-electron distribution in complex
aromatic systems.3 Recently, renewed attention in
cycloarenes has arisen since they serve as models for
graphene pores.4 Kekulene (1) is probably the best
studied member of this family. Its electronic structure
has been the subject of debate for decades,5 being the
Clar model 1a and the annulenoid Kekule structure 1b
of special interest (Figure 1). In fact, properties such as
superaromaticity6,7 have been initially attributed to this
molecule, associated to hypothetically representative
annulenoid structures such as 1b, comprising two
concentric [4n+2] π-electron circuits.
Figure 1. Clar (1a) and Kekule annulenoid (1b) structures
of kekulene
While many theoretical studies on the electronic
structure of cycloarenes have been reported, the
experimental study of their properties has found
limitations due to the extremely challenging synthesis of
this kind of planar, cata-condensed aromatic
macrocyclic systems.2 In fact, the synthesis and
characterization of kekulene by Staab and Diederich in
Scheme 1. Synthetic approach to kekulene by Staab and
Diederich1,8a
Our expertise and continuing interest in the chemistry of
polycyclic aromatic compounds and nanographenes led
us to turn our attention to this captivating molecule.
Thus, here we present our contribution to the study of
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
kekulene through three different, yet related Initial essays were performed in refluxing dioxane using
1
2
3
4
5
6
7
8
achievements: the improved synthesis of 1 by means of
the aryne-mediated construction of a key synthetic
intermediate, the single-molecule imaging of this
fascinating cycloarene by ultrahigh resolution atomic
force microscopy (AFM) and a computational study
including the accurate simulation of the experimentally
observed AFM images.
CsF as the fluoride source, conditions that had been
previously reported for the unusual selective preparation
of non-arylated 9,10-dihydrophenanthrene by reaction of
styrene with benzyne.19 Encouragingly, treatment of 5
with CsF in refluxing dioxane, in the presence of excess
3, resulted in the formation of the expected products 2
and 6, although in modest yield (entry 1). Addition of
18-crown-6 (entry 2) or the use of TBAF as fluoride
source (entry 3) led to poorer results.
As shown in Scheme 1, probably the main drawback of
9
the otherwise superb synthesis of 1 is the preparation of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5,6,8,9-tetrahydrobenzo[m]tetraphene
(2).13
The
construction of the key synthetic intermediate 2, far
from being straightforward, was reported to occur in
four steps, involving relatively harsh reaction conditions
and in a poor overall 2.8% yield (Scheme 2a).1 Our wide
experience in the application of bistriflate 5 and other
bisaryne precursors to the synthesis of diverse PAHs of
interest,14,15 led us to envision an alternative approach to
2 through a double Diels-Alder reaction involving two
molecules of styrene (3) and the 1,4-benzodiyne synthon
4, which would be generated by fluoride induced
elimination from bistriflate 5,16 which is currently
commercially available (Scheme 2b)..
TMS
TfO
OTf
3
+
TMS
CsF, ACN
28%
formally vía 4
5
2
6
Scheme 3. Reaction of bistriflate 5 with CsF in presence of
styrene
Table 1. Optimization of the reaction conditionsa
Molar ratio
5:3:CsF
Scale (mmol
Yield 2+6
Entry
Solvent
5)
(%)b
1
2c
3d
4e
5
Dioxane
Dioxane
Dioxane
ACN
1:5:10
1:5:10
1:5:10
1:5:10
1:5:10
1:2:10
1:25:10
1:5:6
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.4
6
17
11
–
13
20
12
23
20
22
26
28
ACN
6
7f
ACN
ACN
8
ACN
9
ACN
1:5:6
10
11
ACN
1:5:6
Scheme 2. (a) Staab&Diederich’s synthesis of 2:1 i) conc.
HNO3, ∆; ii) PhCHO, piperidine; iii) H2, 90 atm, 10%Pd/C,
∆; iv) Cu, conc. H2SO4, isoamyl nitrite. (b) This work:
aryne-based retrosynthetic approach to 2.
ACN
1:5:6
19
aTypical reaction conditions: reflux under Ar, 16 h, [5] = 0.05 M.
bYield of isolated product (≈ 2:3 mixture of 2 and 6). c18-crown-6
d
(120 mol%) was added. TBAF was used as source of fluoride.
eReaction conducted at room temperature. f[5] = 0.01 M.
The participation of styrenes as unconventional dienes in
Diels-Alder cycloadditions with arynes to yield
dihydrophenanthrenes has been previously reported,
although these transformations are commonly
complicated by secondary reactions such as aryne-
mediated dehydrogenation to give phenanthrenes,17 or
by the concerted ene reaction of the initial Diels-Alder
adduct with a second aryne equivalent to afford arylated
products.18 In our case, such a Diels-Alder/ene cascade
would be particularly problematic, since the ene-
incorporated aryl moiety would contain ortho-disposed
trimethylsilyl and triflate functionalities, being able to
generate new aryne species and giving rise, probably, to
oligomerization processes and complex reaction
mixtures. Despite these possible difficulties, we targeted
the synthesis of 2 by reaction of styrene with 1,4-
bisbenzyne precursor 5 under aryne-forming conditions
(Scheme 3, Table 1).
The use of acetonitrile (ACN) as solvent led to slightly
better yields (entry 5) and, in these conditions, the molar
ratio 5:3:CsF was optimized (entries 5-8). Finally, we
proved that better yields were consistently obtained
when performing the reaction at higher scale (entries 8-
11). The best results were obtained by reaction of 5 (19-
20 mmol) with styrene (3) and CsF (in 1:5:6 molar ratio)
in refluxing acetonitrile, yielding a 2:3 mixture of
tetrahydrobenzotetraphenes 2 and 6 in a reasonable 28%
yield (entry 11). The separation of both isomers was not
easy, but it could be achieved by semi-preparative
supercritical fluid chromatography (SFC)20 and also by
sequential recrystallizations from boiling methanol.
These results can be considered highly remarkable, since
compound 2, a key intermediate in the synthesis of
kekulene (1), is obtained in just one step from
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
commercially available materials, under mild reaction Remarkably, the only isolable compounds detected in
1
2
3
4
5
6
7
8
conditions and with a fourfold increased yield with
respect to that of the previously reported synthesis.
the crude reaction mixtures were 2, 6 and excess styrene
(3).20 Products derived either from dehydrogenation of
2/6 or from Diels−Alder/ene cascade processes were not
observed.21 However, the formation of insoluble
oligomers or polymers derived from aryne-based side
reactions cannot be ruled out. The mechanism proposed
for the formation of 2 (and 6), involves two probably
sequential Diels-Alder/H-migration processes. The
detection of the functionalized dihydrophenanthrene 8 in
some experiments, strongly suggests that the first Diels-
Alder reaction of styrene with monoaryne 7 and the
subsequent H-migration, occur prior to the generation of
the second arynic insaturation in 9 (Scheme 4). Once
compound 2 was conveniently prepared, we proceeded
to complete the synthesis of kekulene (1). After
attempting some new synthetic alternatives based on
Y
X
Y
X
TMS
TfO
F
5
H
Diels-Alder
9
7
8
X = OTf, Y = TMS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
and/or X = TMS, Y = OTf
F
2
6
H
H
Diels-Alder
9
metal-catalyzed
couplings
and/or
olefin
metathesis/isomerization reactions, we decided to rely
on the firmly established route described by Diederich
and Staab,1,8 which in our hands was perfectly
reproducible, even under significantly lower scale
conditions.
Scheme 4. Mechanistic proposal for the formation of 2/6
Figure 2. Experimental AFM images of kekulene (1) on Cu(111). (a-c) Constant-height AFM images with a CO
functionalized tip, amplitude A = 1 Å, sample voltage V = 0 V. We approached the tip by z = 1.6 Å in (a), 1.9 Å in (b) and
2.2 Å in (c) with respect to the STM setpoint of V = 0.1 V, I = 1 pA on the bare Cu(111) surface. (d-e) Corresponding
Laplace-filtered images.
With kekulene (1) in hand we identified the opportunity
to visualize its molecular structure by ultrahigh resolution
AFM,22 a state-of-the-art technique for the single-
molecule study of planar, conjugated systems. As
recently demonstrated this technique, in combination
with STM, has become a powerful tool for the
elucidation and study of individual molecules.23 In order
to increase the sublimation rate with respect to the
fragmentation rate the material was sublimated by rapid
heating24a from a Si wafer,24b onto a Cu(111) substrate,
holding the sample at T = 10 K during deposition. The
large size and thus high sublimation temperature of
kekulene was expected to result in fragmentation and, in
fact, the preparation resulted mostly in small and often
mobile molecules on the surface. However, we found a
few molecules of the expected hexagonal shape and size
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
of kekulene. Constant-height AFM images of the qualitative resolution of bond-order differences.
1
2
3
4
5
6
7
8
molecule adsorbed on Cu(111) with a CO functionalized
tip22,25-28 were recorded at different heights (Figure 2)
with decreasing tip to sample distance from Fig. 2a to 2c.
Corresponding Laplace filtered images are shown in Fig.
2d to 2f, respectively. From the AFM images, the
molecular structure of kekulene (1) was resolved. In
addition, details of the contrast can be related to bond
order. Resolving the bond-order related contrast is
challenging at the periphery of molecules because of the
non-planar background from van der Waals and
electrostatic forces.27,29 However, bonds that experience
similar background forces are comparable, allowing
Increased bond order results in brighter appearance at
moderate tip heights and shortened appearance of bonds
at small tip heights.27 In the case of kekulene (1), the
peripheral C(H)–C(H) bonds appear as the overall
brightest bonds at moderate tip height, i.e., in Fig. 2a,b,
and as the shortest bonds at small tip height, i.e., in Fig.
2c. Both observations indicate that these are the bonds of
the highest bond order within the kekulene structure,
which is in agreement with previous experimental
evidence obtained by X-ray diffraction (XRD) studies of
single crystals of 1.8b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. PPM simulated AFM images with an amplitude of A = 1 Å computed with a PBE QM/MM electrostatic potential
interacting with a classical dz2 -like quadrupole tip (Qdz2=-0.25 e- Å −2) with a bending stiffness of 0.35 N/m at z= 3.4 Å in
(a), 3.3 Å in (b) and 3 Å in (c) with respect to the molecular plane. All distances are in Å.
To gain further insight into the interpretation of the AFM match to the experimental images was achieved by a dz2-
images in connection with the molecular structure of 1, like quadrupole tip33 with Qdz2 = -0.25 e-/A2 and a bending
we computed the kekulene molecule both in the gas phase constant of k = 0.35 N/m, see Figure 3.34
and on the Cu(111) surface and performed simulations of
AFM images.20 Calculations in the gas-phase at the
a
b
1.40
1.42
1.39 1.46
1.40
1.42
1.38 1.45
1.36
1.35
B3LYP-def2-TZVP level30 reveal that the molecule
possesses D3d symmetry since the hydrogen atoms of the
inner cavity or pore present a slight distortion out of the
molecular plane due to steric hindrance. Remarkably, the
calculated C–C bond distances reproduce the
experimental solid-state XRD values within 0.01 Å
(Figure 4). This bonding pattern, which is also reproduced
by on-surface calculations, matches perfectly the
predictions of the π-sextet rule31 and supports the Clar
model 1a, with the highest possible number of disjoint
aromatic π-sextets (six) as the most representative
structure of kekulene. Thus, despite its 48 π electrons (6n
π electrons) kekulene is far from being “fully benzenoid”,
as the π electrons are not highly delocalized. In fact, 1
possesses an unusually high calculated HOMO-LUMO
gap of 3.55 eV (B3LYP-def2-TZVP level), similar to that
calculated for the much smaller anthracene molecule
(3.56 eV). Finally, simulations of the AFM images were
performed with a Molecular Mechanics (MM) model as
implemented in the Probe Particle Model (PPM)
software.20,28,32 We computed images with the
experimental amplitude of 1.0 Å and with different
bending constants, k, ranging from 0.15 to 0.60 N/m, and
uncharged, monopole and quadrupole tips. The best
1.44
1.44
Figure 4. (a) Molecular structure of kekulene (1) computed
at the B3LYP-def2-TZVP level in vacuum. (b)
Experimental structure from XRD, C2/c space group
symmetry. The colors grade with distance from 1.33 Å (red)
to 1.40 Å (white) and to 1.47 Å (blue). Bond lengths are in
Å.
In conclusion, this work provides
a
significant
contribution to the synthesis of kekulene (1) based on the
improved preparation of the key intermediate 5,6,8,9-
tetrahydrobenzo[m]tetraphene (2) by means of aryne
chemistry. The modified protocol has been applied to the
actual synthesis of 1, which, to the best of our
knowledge, had not been synthesized neither
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
Y.; Lu, X.; Li, G.; Wu, J. Global Aromaticity in Macrocyclic
Polyradicaloids: Hückel ’ s Rule or Baird ’ s Rule? Acc. Chem. Res.
2019, 52, 2309-2321.
(4) (a) Robertson, A. W.; Lee, G.-D.; He, K.; Gong, C.; Chen, Q.;
Yoon, E.; Kirkland, A. I.; Warner, J. H. Atomic Structure of Graphene
Subnanometer Pores. ACS Nano, 2015, 9, 11599–11607. (b) Beser, U.;
Kastler, M.; Maghsoumi, A.; Wagner, M.; Castiglioni, C.; Tommasini,
M.; Narita, A.; Feng X.; Müllen, K. A C216-Nanographene Molecule
with Defined Cavity as Extended Coronoid. J. Am. Chem. Soc. 2016,
138, 4322–4325. (c) Hieulle, J.; Carbonell-Sanromà, E.; Vilas-
experimentally studied since the seminal work by Staab
1
2
3
4
5
6
7
8
and Diederich in the early eighties. With this material in
hand, the structure of individual molecules of kekulene
(1) was nicely resolved by ultrahigh resolution AFM. The
computational study of kekulene (1) in vacuum and on
the Cu(111) surface and the successful simulation of the
experimental single-molecule AFM images, provided
further evidences of a bonding pattern for kekulene
which matches with the molecular structure predicted by
Clar’s π-sextet rule.
Varela, M.; García-Lekue, A.; Guitián, E.; Peña, D.; Pascual, J. I.
On-surface Route for Producing Planar Nanographenes with
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Azulene Moieties. Nano Lett. 2018, 18, 418-423. (d) Moreno, C.;
Vilas-Varela, M.; Kretz, B.; García-Lekue, A.; Costache, M. V.;
Paradinas, M.; Panighel, M.; Ceballos, G.; Valenzuela, S. O.; Peña, D.;
Mugarza, A. Bottom-up Synthesis of Multifunctional Nanoporous
Graphene Science 2018, 360, 199-203. (e) Xu, K.; Urgel, J. I.; Eimre,
K., Giovannantonio, M. D.; Keerthi, A.; Komber, H.; Wang, S.;
Narita, A.; Berger, R.; Ruffieux, P.; Pignedoli, C. A.; Liu, J.;
Müllen, K.; Fasel, R.; Feng, X. On-Surface Synthesis of a
Nonplanar Porous Nanographene. J. Am. Chem. Soc. 2019, 141,
ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website. Experimental procedures,
synthesis,
characterization,
AFM
imaging
and
computational details (PDF).
AUTHOR INFORMATION
Corresponding Author
7726-7730.
(5) For seminal contributions see: (a) McWeeny, R. The
Diamagnetic Anisotropy of Large Aromatic Systems: III Structures
with Hexagonal Symmetry. J. Phys. Chem. A 1951, 921-930. (b)
Aihara, J. On the Number of Aromatic Sextets in a Benzenoid
Hydrocarbon. Bull. Chem. Soc. Jpn. 1976, 49, 1429–14230.
dolores.perez@usc.es
diego.pena@usc.es
ACKNOWLEDGMENT
(6) (a) Cioslowski, J.; O ’ Connor, P. B.; Fleischmann, E. D. Is
Superbenzene Superaromatic? J. Am. Chem. Soc. 1991, 113, 1086-
1089. (b) Aihara, J. Is Superaromaticity a Fact or an Artifact? The
Kekulene Problem. J. Am. Chem. Soc. 1992, 114, 865–868. (c) Jiao,
H.; Schleyer, P. R. Is Kekulene Really Superaromatic?. Angew. Chem.
Int. Ed. Engl. 1996, 35, 2383–2386. (d) Zhou, Z. Are kekulene,
coronene, and corannulene tetraanion superaromatic? Theoretical
examination using hardness indices. J. Phys. Org. Chem. 1995, 8, 103–
107. (e) Aihara, J.; Makino, M.; Ishida, T.; Dias, J. R. Analytical Study
of Superaromaticity in Cycloarenes and Related Coronoid
Hydrocarbons. J. Phys. Chem. A 2013, 117, 4688–4697.
(7) The synthesis of two structurally related macrocyclic
polyradicaloids, with “annulene-within-an-annulene” structure and
unusual global aromaticity, has been recently reported: Liu, C.;
Sandoval-Salinas, M. E.; Hong, Y.; Gopalaskrishna, T. Y.; Phan, H.;
Aratani, N.; Herng, T. S.; Ding, J.; Yamada, H.; Kim, D.; Casanova,
D.; Wu, J. Macrocyclic Polyradicaloids with Unusual Super-ring
Structure and Global Aromaticity. Chem 2018, 4, 1–10.
(8) (a) Diederich, F.; Staab, H. A. Benzenoid versus Annulenoid
Aromaticity : Synthesis and Properties of Kekulene. Angew. Chem. Int.
Ed. Engl. 1978, 17, 372–374. (b) Krieger, C. Diederich, F.;
Schweitzer, D. Staab, H. A. Molecular Structure and Spectroscopic
Properties of Kekulene. Angew. Chem. Int Ed. Engl. 1979, 18, 669-
701. (c) Staab, H. A.; Diederich, F.; Krieger, C.; Schweitzer, D.
Molecular Structure and Spectroscopic Properties of Kekulene. Chem.
Ber. 1983, 116, 3504–3512.
Financial support from the Spanish Agencia Estatal de
Investigación (CTQ2016-78157-R and MAT2016-78293-
C6-3-R; AEI/FEDER, UE), Xunta de Galicia (Centro
singular de investigación de Galicia accreditation 2016-
2019, ED431G/09) and the European Union (European
Regional Development Fund-ERDF), and the ERC
Consolidator Grant AMSEL (682144) as well as from the
Portuguese Foundation for Science and Technology (FCT),
under
the
projects
PTDC/FIS-NAN/4662/2014,
Aveiro Institute of
IF/00894/2015, and CICECO
-
Materials, FCT Ref. UID/CTM/50011/2019, is gratefully
acknowledged. IP thanks Xunta de Galicia and European
Union (European Social Fund, ESF) for the award of a pre-
doctoral fellowship. In addition, MMF would like to thank
the Project HPC-EUROPA3 (INFRAIA-2016-1-730897)
and the Barcelona Supercomputing Center for computer
resources and technical support. This paper is dedicated to
Prof. François Diederich and to the memory of Prof. Heinz
A. Staab in honor of their outstanding achievements in the
synthesis and study of kekulene.
(9)
Funhoff,
D.
J.
H.;
Staab,
H.
A.
REFERENCES
Cyclo[d.e.d.e.e.d.e.d.e.e.]decakisbenzene, a New Cycloarene. Angew.
Chem. Int. Ed. Engl. 1986, 25, 742–744.
(1) Staab, H. A.; Diederich, F. Synthesis of Kekulene. Chem. Ber.
1983, 116, 3487−3503.
(2) For an excellent recent review, see: Buttrick, J. C.; King, B. T.
Kekulenes, Cycloarenes, and Heterocycloarenes: Addressing
Electronic Structure and Aromaticity through Experiments and
Calculations. Chem. Soc. Rev. 2017, 46, 7−20.
(3) (a) Aihara, J. π-Electron Currents Induced in Polycyclic
Benzenoid Hydrocarbons and their Relationship to Clar Structures. J.
Phys. Chem. A 2003, 107, 11553-11557. (b) Randic, M. Aromaticity of
Polycyclic Conjugated Hydrocarbons Chem. Rev. 2003, 103,
3449−3605. (c) Aihara, J.; Makin, M. Constrained Clar Formulas of
Coronoid Hydrocarbons. J. Phys. Chem. A 2014, 118, 1258−1266. (d)
Stepien, M. An Aromatic Riddle: Decoupling Annulene Conjugation
in Coronoid Macrocycles. Chem 2018, 4, 1481-1491. (e) Liu, C.; Ni,
(10) Kumar, B.; Viboh, R. L.; Bonifacio, M. C.; Thompson, W. B.;
Buttrick, J. C.; Westlake, B. C.; Kim, M.-S.; Zoellner, R. W.;
Varganov, S. A.; Mörschel, P.; Teteruk, J.; Schmidt, M. U.; King, B.
T. Septulene: The Heptagonal Homologue of Kekulene. Angew. Chem.
Int. Ed. 2012, 51, 12795–12800.
(11) Majewski, M. A.; Hong, Y.; Lis, T.; Gregolinski, J.;
Chmielewski, P. J.; Cybinska, J.; Kim, D.; Stepien, M. Octulene: A
Hyperbolic Molecular Belt that Binds Chloride Anions. Angew. Chem.
Int. Ed. 2016, 55, 14072–14076.
(12) Schweitzer, D.; Hausser, K. H.; Vogler, H.; Diederich, F.;
Staab, H. A. Electronic Properties of Kekulene. Mol. Phys. 1982, 46,
1141–1153.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
(13) This specific, partially hydrogenated PAH, is needed to
Riss, A.; Mowbray, D. J.; Etkin, G.; Pedramrazi, Z.; Tsai, H.-Z.;
guarantee the conformational flexibility required for the penultimate
step in the synthesis of kekulene (a double photochemical
cycloisomerization; see ref. 1 for details).
Rubio, A.; Crommie, M. F.; Fischer, F. R. Direct Imaging of Covalent
Bond Structure in Single-Molecule Chemical Reactions. Science 2013,
340, 1434-1437. (e) Rogers, C.; Chen, C.; Pedramrazi, Z.; Omrani, A.
A.; Tsai, H.-Z.; Jung, H. S.; Lin, S.; Crommie, M. F.; Fischer, F. R.
Closing the Nanographene Gap: Surface-Assisted Synthesis of
Peripentacene from 6,6’-Bipentacene Precursors. Angew. Chem. Int.
Ed. 2015, 54, 15143-15146. (f) Kawai, S.; Haapasilta, V.; Lindner, B.
D.; Tahara, K.; Spijker, P.; Buitendijk, J. A.; Pawlak, R.; Meier, T.;
Tobe, Y.; Foster, A. S.; Meyer, E. Thermal Control of Sequential On-
Surface Transformation of a Hydrocarbon Molecule on a Copper
Surface. Nature Commun. 2016, 7, 12711. (g) Hieulle, J.; Carbonell-
Sanromà, E.; Vilas-Varela, M.; García-Lekue, A.; Guitián, E.; Peña,
D.; Pascual, J. I. On-Surface Route for Producing Planar
Nanographenes with Azulene Moieties. Nano Lett. 2018, 18, 418-423.
(h) Fan, Q.; Werner, S.; Tschakert, J.; Ebeling, D.; Schirmeisen, A.;
Hilt, G.; Hieringer, W. Gottfried, W. Precise Monoselective Aromatic
C–H Bond Activation by Chemisorption of Meta-Aryne on a Metal
Surface. J. Am. Chem. Soc. 2018, 140, 7526-7532. (i) Mishra, S.;
Beyer, D.; Eimre, K.; Liu, J.; Berger, R.; Gröning, O.; Pignedoli, C.
A.; Müllen, K.; Fasel, R.; Feng, X.; Ruffieux, P. Synthesis and
Characterization of π-Extended Triangulene. J. Am. Chem. Soc. 2019,
141, 10621-10625. (j) Su, J.; Telychko, M.; Hu, P.; Macam, G.;
Mutombo, P.; Zhang, H.; Bao, Y.; Cheng, F.; Huang, Z.-Q.; Qiu, Z.;
Tan, S. J. R.; Lin, H.; Jelínek, P.; Chuang, F.-C.; Wu, J.; Lu, J.
1
2
3
4
5
6
7
8
(14) (a) Schuler, B.; Collazos, S.; Gross, L.; Meyer, G.; Pérez, D.;
Guitián, E.; Peña, D. From Perylene to
a 22-Ring Aromatic
Hydrocarbon in One-Pot. Angew. Chem. Int. Ed. 2014, 53, 9004–9006.
(b) Rodríguez-Lojo, D.; Peña, D.; Pérez, D.; Guitián, E. Large Phenyl-
Substituted Acenes by Cycloaddition Reactions of the 2,6-
Naphthodiyne Synthon Chem. Commun. 2015, 51, 5418–5420. (c)
Rodríguez-Lojo, D.; Peña, D.; Pérez, D.; Guitián, E. Straightforward
Synthesis of Novel Acene-Based Aryne Precursors, Synlett 2015, 26,
1633–1637. (d) Pozo, I.; Cobas, A.; Peña, D.; Guitián, E.; Pérez, D.
1,7-Naphthodiyne: a New Platform for the Synthesis of Novel,
Sterically Congested PAHs Chem. Commun. 2016, 52, 5534–5537. (e)
Garcia, D., Rodríguez-Pérez, L.; Herranz, M. A.; Peña, D.; Guitián, E.;
Bailey, S.; Al-Galiby, Q.; Noori, M.; Lambert, C. J.; Perez, D.; Martín,
N. A C60-Aryne Building Block: Synthesis of a Hybrid All-Carbon
Nanostructure. Chem. Commun. 2016, 52, 6677–6680. (f) Krüger, J.;
García, F.; Eisenhut, F.; Skidin, D.; Alonso, J. M.; Guitián, E.; Pérez,
D.; Cuniberti, G.; Moresco, F.; Peña, D. Decacene: On-Surface
Generation Angew. Chem. Int. Ed., 2017, 56, 11945–11948. (g)
Schulz, F.; García, F.; Kaiser, K.; Pérez, D.; Guitián, E.; Gross, L.;
Peña, D. Exploring a Route to Cyclic Acenes by On-Surface Synthesis.
Angew. Chem. Int. Ed., 2019, 58, 9038-9042.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15) For representative examples by other authors, see: (a) Li, J.;
Zhao, Y.; Lu, J.; Li, G.; Zhang, J.; Zhao, Y.; Sun, X.; Zhang, Q.
Double [4+2] Cycloaddition Reaction to Approach a Large Acene with
Even-Number Linearly Fused Benzene Rings: 6,9,16,19-Tetraphenyl-
1.20,4.5,10.11,14.15-Tetrabenzooctatwistacene. J. Org. Chem. 2015,
80, 109–113. (b) Kumarasinhe, K. G. U. R.; Fronczek, F. R.; Valle, H.
U.; Sygula, A. Bis-corannuleno-anthracene: An Angularly Fused
Atomically
Precise
Bottom-up
Synthesis
of
π-Extended
[5]Triangulene. Sci. Adv. 2019, 5, eaav7717. (k) Sánchez-Grande, A.;
de la Torre, B.; Santos, J.; Cirera, B.; Lauwaet, K.; Chutora, T.;
Edalatmanesh, S.; Mutombo, P.; Rosen, J.; Zbořil, R.; Miranda, R.;
Björk, J.; Jelínek, P.; Martín, N.; Écija, D. On-Surface Synthesis of
Ethynylene-Bridged Anthracene Polymers. Angew. Chem. Int. Ed.
2019, 58, 6559-6563.
(24) (a) Rapenne, G., Grill, L., Zambelli, T., Stojkovic, S.M.,
Ample, F., Moresco, F. and Joachim, C. Launching and landing single
molecular wheelbarrows on a Cu (100) surface. Chem. Phys. Lett.
2006, 431, 219-222. (b) Schuler, B.; Meyer, G.; Peña, D.; Mullins, O.
C.; Gross, L. Unraveling the Molecular Structures of Asphaltenes by
Atomic Force Microscopy J. Am. Chem. Soc. 2015, 137, 9870–9876.
(25) Gross, L.; Mohn, F.; Moll, N.; Meyer, G.; Ebel, R.; Abdel-
Mageed, W. M.; Jaspars, M. Organic Structure Determination Using
Atomic Resolution Scanning Probe Microscopy. Nat. Chem. 2010, 2,
821–825.
(26) Bartels, L.; Meyer, G.; Rieder, K. H. Controlled Vertical
Manipulation of Single CO molecules with the Scanning Tunneling
Microscope: A Route to Chemical Contrast Appl. Phys. Lett. 1997, 71,
213–215.
(27) Gross, L.; Mohn, F. Moll, N.; Schuler, B.; Criado, A.; Guitián,
E.; Peña, D. A. Gourdon, G. Meyer. Bond-Order Discrimination by
Atomic Force Microscopy. Science, 2012, 337, 1326-1329.
(28) Hapala, P.; Kichin, G.; Wagner, C.; Tautz, F. S.; Temirov, R.;
Jelínek, P. Mechanism of High-Resolution STM/AFM Imaging with
Functionalized Tips. Phys. Rev. B 2014, 90, 085421.
Pentacene as
a
Precursor for Barrelene-Tethered Receptors for
Fullerene. Org. Lett. 2016, 18, 3054–3057.
(16) Duong, H. M.; Bendikov, M.; Steiger, D.; Zhang, Q.; Sonmez,
G.; Yamada, J.; Wudl, F. Efficient Synthesis of a Novel, Twistedand
Stable, Electroluminescent “Twistacene”. Org. Lett. 2003, 5, 4433–
4436.
(17) (a) Wolthuis, E.; Cady, W. Reaction of Benzyne with α-
Methylstyrene Angew. Chem. Int. Ed., 1967, 6, 555–556. (b) Harrison,
R.; Heaney, H.; Jablonski, J. M.; Mason, K. G.; Sketchley, J. M. Aryne
Chemistry. Part XVIII. Some Reactions of Tetrahalogenobenzyneswith
Styrene and Substituted Styrenes J. Chem. Soc. C, 1969, 1684–1689.
(18) (a) Dilling, W. L. The Reaction of Benzyne with Styrene
Tetrahedron Lett. 1966, 9, 939–941. (b) Bhojgude, S. S.; Bhunia, A.;
Gonnade, R. G.; Biju, A. T. Efficient Synthesis of 9–
Aryldihydrophenanthrenes by a Cascade Reaction Involving Arynes
and Styrenes, Org. Lett. 2014, 16, 676–679. (c) Bhojgude, S. S.;
Bhunia, A.; Biju, A. T. Employing Arynes in Diels-Alder Reactions
and Transition-Metal-Free Multicomponent Coupling and Arylation
Reactions Acc. Chem. Res. 2016, 49, 1658-1670.
(19) Chen, Z.; Han, X.; Liang, J. H.; Yin, J.; Yu, G. A.; Liu, S. H.
Cycloaddition Reactions of Benzyne with Olefins. Chinese Chem. Lett.
2014, 25, 1535–1539.
(29) Majzik, Z.; Pavliček, N.; Vilas-Varela, M.; Pérez, D.; Moll, N.;
Guitián, E.; Meyer, G.; Peña, D.; Gross, L. Studying an Antiaromatic
Polycyclic Hydrocarbon Adsorbed on Different Surfaces. Nature
Commun. 2018, 9, 1198.
(20) See Supporting Information for details.
(21) In some experiments performed in large scale, trace amounts of
a monophenylated product were detected by mass spectrometry.
(22) Gross, L.; Mohn, F.; Moll, N.; Liljeroth, P.; Meyer, G. The
(30) This level of calculations has been found to reproduced
quantitatively key electronic properties of other PAHs, for instance: (a)
Cortizo-Lacalle, D.; Mora-Fuentes, J. P.; Strutynski, K.; Saeki, A.;
Melle-Franco, M.; Mateo-Alonso, A. Monodisperse N-Doped
Graphene Nanoribbons Reaching 7.7 Nanometers in Length. Angew.
Chem. Int. Ed. 2018, 57, 703–708. (b) Belén, M. A.; Cortizo-Lacalle,
D.; Conzalvez, C.; Olano, M.; Atxabal, A.; Sun, X.; Melle-Franco, M.;
Hueso, L. E.; Mateo-Alonso A. An Electron-Conducting Pyrene-Fused
Phenazinothiadiazole. Chem. Commun. 2015, 51, 10754–10757.
(31) (a) Clar, E. The Aromatic Sextet, 1972, Wiley, New York. (b)
Solá, M.; Forty years of Clar’s aromatic π-sextet rule. Front. Chem.
2013, 1, 22.
Chemical Structure of
a Molecule Resolved by Atomic Force
Microscopy. Science 2009, 325, 1110–1114.
(23) (a) Gross, L.; Mohn, F.; Moll, N.; Liljeroth, P.; Meyer, G.
Atomic Force Microscopy for Molecular Structure Ellucidation.
Angew. Chem. Int. Ed. 2018, 57, 3888–3908 and references cited
therein; (b) Peña, D.; Pavlicek, N.; Schuler, B.; Moll, N.; Pérez, D.;
Guitián, E.; Meyer, G.; Gross L. in On-Surface Synthesis II. Advances
in Atom and Single Molecule Machines (Eds.: D. de Oteyza, C.
Rogero), Springer, Cham, 2018, pp. 209-227. (c) Fatayer, S.; Albrecht,
F.; Zhang, Y.; Urbonas, D.; Peña, D.; Noll, N.; Gross, L. Molecular
structure elucidation with charge-state control. Science 2019, 365, 142-
145. (d) de Oteyza, D. G.; Gorman, P.; Chen, Y.-C.; Wickenburg, S.;
(32) Hapala, P.; Temirov, R.; Tautz, S.; Jeníkel, P. Origin of High-
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
Resolution IETS-STM Images of Organic Molecules with
Functionalized Tips Phys. Rev. Lett. 2014, 113, 226101.
from High-Resolution Scanning Probe Images. Nature Commun. 2016,
7, 11560.
(34) For values of the measured and simulated apparent bond
lengths see Supporting Information.
1
2
3
4
5
6
(33) Similar to previous findings: (a) Ellner, M.; Pavliček, N.; Pou,
P.; Schuler, B.; Moll, N.; Meyer, G.; Gross, L.: Pérez, R. The Electric
Field of CO Tips and Its Relevance for Atomic Force Microscopy.
Nano Lett. 2016, 16, 1974–1980. (b) Hapala, P.; Svec, M.; Stetsovych,
O.; Heijden, N. J.; Ondracek, M.; Lit, J.; Mutombo, P.; Swart, I.;
Jelínek, P. Mapping the Electrostatic Force Field of Single Molecules
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. (a) Molecular structure of kekulene (1) computed at the B3LYP-def2-TZVP level in vacuum. (b)
Experimental structure from XRD, C2/c space group symmetry. The colors grade with distance from 1.33 Å
(red) to 1.40 Å (white) and to 1.47 Å (blue). Bond lengths are in Å
81x43mm (300 x 300 DPI)
ACS Paragon Plus Environment