The side chain makes the difference: Investigation of the 2D self-assembly of 1,3,5-tris[4-(4-pyridinyl)phenyl]benzene derivatives by scanning tunneling microscopy

Article abstract of DOI:10.1002/ejoc.201402178

Flexible and straightforward syntheses of a series of D_3h- or C_3h-symmetrical star-shaped compounds with pyridine end groups are reported. In all cases, the acid-mediated cyclocondensations of the corresponding aryl methyl ketone provided the central benzene ring. For the preceding preparation of the functionalized compound arms, Suzuki couplings were applied. The crucial introduction of the pyridine C-2 and C-6 substituents occurred by Fe(acac)₃-catalyzed alkylations (acac = acetylacetonate). The preparation of the C₃-symmetrical compound involved an alternating sequence of halogenations and coupling reactions. The self-assembly behavior of the four resulting star-shaped compounds at the interface between 1-phenyloctane and the basal plane of highly oriented pyrolytic graphite (HOPG) was studied by scanning tunnelling microscopy (STM). We found self-assembled monolayers with structures strongly dependent on the substitution patterns of the investigated compounds. The reduction of the symmetry from a D_3h- to a C_3h-symmetrical compound led to an entirely different self-assembly behavior with the change from a hexagonal to a lamellar arrangement.

Full text of DOI:10.1002/ejoc.201402178

FULL PAPER
DOI: 10.1002/ejoc.201402178
The Side Chain Makes the Difference: Investigation of the 2D Self-Assembly
of 1,3,5-Tris[4-(4-pyridinyl)phenyl]benzene Derivatives by Scanning Tunneling
Microscopy
Daniel Trawny,[a] Lucie Vandromme,[a] Jürgen P. Rabe,*[b] and Hans-Ulrich Reissig*[a]
Keywords: C–C coupling / Monolayers / Star-shaped compounds / Self-assembly / Scanning probe microscopy
Flexible and straightforward syntheses of a series of D3h- or
C3h-symmetrical star-shaped compounds with pyridine end
groups are reported. In all cases, the acid-mediated cyclocon-
densations of the corresponding aryl methyl ketone provided
the central benzene ring. For the preceding preparation of
the functionalized compound arms, Suzuki couplings were
applied. The crucial introduction of the pyridine C-2 and C-
6 substituents occurred by Fe(acac)3-catalyzed alkylations
(acac = acetylacetonate). The preparation of the C3-symmet-
nations and coupling reactions. The self-assembly behavior
of the four resulting star-shaped compounds at the interface
between 1-phenyloctane and the basal plane of highly ori-
ented pyrolytic graphite (HOPG) was studied by scanning
tunnelling microscopy (STM). We found self-assembled
monolayers with structures strongly dependent on the substi-
tution patterns of the investigated compounds. The reduction
of the symmetry from a D3h- to a C3h-symmetrical compound
led to an entirely different self-assembly behavior with the
rical compound involved an alternating sequence of haloge- change from a hexagonal to a lamellar arrangement.
The investigation of the self-assembly of C3-symmetrical
Introduction
(“star-shaped”) compounds with pyridine end groups at the
The self-assembly of molecules into well-defined supra-
solution–graphite interface is particularly interesting as the
molecular architectures is a fundamental principle in nature
molecular C3 scaffold fits perfectly to the graphite lattice.
In previous studies, we reported a new C3-symmetrical tris-
(oxazole) derivative and its ability to form self-assembled
and can be found in many biological and chemical pro-
cesses.[1] Over the last decade, it became possible to con-
monolayers.[6] Although we expected the formation of a
hexagonal arrangement, the C3h-symmetrical trisoxazole
derivative self-assembled into long chains, and a lamellar
lattice was observed. A literature analysis showed that the
self-assembly of D3h- and C3h-symmetrical molecules has
rarely been investigated.[7] To clarify the influence of the
substitution pattern of star-shaped compounds, we planned
to prepare a series of model compounds with D3h or C3h
symmetry and to investigate their self-assembly by STM.
The different pyridyl end groups offer additional options
for further experiments at interfaces.
The preparation of this type of compound can be envi-
sioned by three synthetic strategies, as depicted in
Scheme 1. The star-shaped pyridine derivatives consist of
three parts: ligands, spacers, and a core unit. Pathways A
and B (Scheme 1) exemplify two common approaches that
use coupling reactions such as Sonogashira or Suzuki reac-
tions to connect the core, spacer, and ligand moieties. The
spacer moiety may be either at the core unit (pathway A)
or at the ligand (pathway B).[8] The third strategy, is illus-
trated by pathway C (Scheme 1), which involves a trimeri-
zation process to construct the central core from three func-
tional ligand–spacer units. One option to achieve this goal
is the cyclocondensation reaction of an aryl methyl ketone
struct molecular architectures with nanometer precision for
technological applications, for example, in organic elec-
tronics[2] and molecular machines.[3] Supramolecular archi-
tectures at solid–liquid interfaces have been widely studied
by scanning tunneling microscopy (STM), which is a
powerful tool for investigation of the self-assembly of two-
dimensional adsorbates.[4] The application of computa-
tional molecular dynamic methods makes it possible to pre-
dict self-assembly with increasing accuracy, but it is still a
demanding task to anticipate and to control the 2D ar-
rangement of molecular components.[5] Precise and system-
atic investigations of molecule-to-molecule interactions
with STM could lead to an improved understanding of the
complex self-assembly processes.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustraße 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
http://www.bcp.fu-berlin.de/en/chemie/chemie/forschung/
OrgChem/reissig/index.html
[b] Institut für Physik, Humboldt Universität zu Berlin,
Newtonstraße 15, 12489 Berlin, Germany
E-mail: rabe@physik.hu-berlin.de
http://www.physik.hu-berlin.de/pmm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402178.
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to form the central benzene ring by three subsequent aldol poor solubility of 1, it was not possible to obtain reasonable
condensation steps.[9] In this report, we have exclusively fol- NMR spectra; however, the identity of 1 was clearly proven
lowed pathway C and prepared the four desired star-shaped by mass spectrometry and by the STM investigations (see
1,3,5-tris[4-(4-pyridinyl)phenyl]benzene derivatives 1–4, below).
which consist of identical core units but are connected to
differently substituted pyridine end groups (Scheme 2). We
describe the synthesis of these compounds by straightfor-
ward transformations such as iron-catalyzed couplings of
alkyl Grignard reagents,[10] halogenation reactions,[11] and
the final acid-promoted cyclocondensation reaction of the
corresponding methyl ketone derivatives.[12] The model
compounds 1–4 showed remarkably different self-assembly
at the graphite/phenyloctane solution interface as proven by
STM investigations.
Scheme 3. Synthesis of D3h-symmetrical star-shaped compound 1.
From the hexachloro-substituted compound 1, we at-
tempted to perform an iron-catalyzed alkylation reaction[10]
to obtain the corresponding hexaalkyl-substituted products
2 and 3 (Scheme 4), as was successfully applied in our pre-
vious published examples.[13] However, the poor solubility
of these compounds or their preceding intermediates was
problematic, and no full conversion was observed.
Scheme 1. Three strategies for the synthesis of star-shaped com-
pounds with pyridine end groups.
Scheme 4. Attempts to prepare alkyl-bearing D3h-symmetrical star-
shaped compounds 2 and 3 from precursor 1.
The silicon tetrachloride mediated cyclocondensation of
14 and 15 to the desired star-shaped products 2 and 3 offers
an alternative route (Scheme 5). Our synthesis started with
the Suzuki coupling of 2,6-dichloro-4-iodopyridine and (4-
formylphenyl)boronic acid to quantitatively yield aldehyde
6, which was then treated with trimethyl orthoformate at
50 °C for 4 h to furnish the corresponding acetal 7 in 97%
yield. Subsequently, the Fe(acac)3-catalyzed (acac = acetyl-
acetonate) reactions with decylmagnesium bromide or do-
decylmagnesium bromide successfully afforded the two 2,6-
dialkyl-substituted pyridine derivatives 8 and 9 in good
yields. Deprotection by treatment with trifluoroacetic acid
(TFA) resulted in the quantitative formation of aldehydes
Scheme 2. Target compounds 1–4 required for STM studies.
Results and Discussion
The concept for the preparation of the 2,6-disubstituted 10 and 11, and the addition of methylmagnesium bromide
pyridines was reported previously.[13] Starting from 2,6- afforded alcohols 12 and 13. They were subsequently oxid-
dichloro-4-iodopyridine and (4-acetylphenyl)boronic acid, a ized with Dess–Martin periodinane to give the cyclocon-
Suzuki coupling with Pd(PPh3)4 as catalyst furnished aryl densation precursors 14 and 15 in good overall yields. In
methyl ketone 5 in quantitative yield (Scheme 3). The cy- the final step, these aryl methyl ketones were again treated
clocondensation precursor 5 was then treated with silicon with silicon tetrachloride in ethanol to give the desired
tetrachloride at 0 °C in ethanol[12a] to afford the first desired hexaalkyl-substituted star-shaped compounds 2 and 3 in
star-shaped compound 1 in 96% yield. Owing to the very moderate yields. Owing to solubility problems, it was not
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2D Self-Assembly of 1,3,5-Tris[4-(4-pyridinyl)phenyl]benzene Derivatives
possible to record well-resolved NMR spectra. However,
1
the H NMR spectra clearly indicated that 2 and 3 were
produced. In addition, the identity of the products was
shown by mass spectrometry and by the STM studies (see
below).
The synthesis of the C3h-symmetrical star-shaped com-
pound 4 was achieved by similar methods; however, a modi-
fication has to be realized to establish the lower symmetry.
A chlorination reaction was implemented into the route to
the unsymmetrical intermediate 18, which is the key inter-
mediate for the synthesis of C3h-symmetrical star-shaped
compounds (Scheme 6). The Suzuki coupling of 4-bromo-
pyridine and (4-formylphenyl)boronic acid provided alde-
hyde 16 in quantitative yield. The treatment of 16 with tri-
methyl orthoformate gave acetal 17 in high yield. The sub-
sequent chlorination was performed under the conditions
described by Gros and Fort.[11] According to their method,
the lithiation reaction selectively occurred at C-2 to afford
the halogenated pyridine derivative 18 in moderate yield. A
second Suzuki coupling with phenylboronic acid furnished
the 2-phenyl-substituted derivative 19 in 87% yield. Under
the conditions mentioned above, a second chlorination was
performed to afford chlorinated compound 20 in 56% yield.
The Fe(acac)3-catalyzed reaction with decylmagnesium
bromide provided the 2,6-disubstituted pyridine derivative
21 in good yield. Deprotection with TFA furnished alde-
hyde 22 almost quantitatively, and reaction with methyl
Grignard reagent followed by oxidation of the resulting
Scheme 5. Synthesis of alkyl-substituted D3h-symmetrical star-
shaped compounds 2 and 3. DMP = Dess–Martin periodinane;
NMP = N-methylpyrrolidone.
Scheme 6. Synthesis of C3h-symmetrical star-shaped compound 4 with alkyl and phenyl substituents. 2-DMAE = 2-(dimethylamino)-
ethanol; DMP = Dess–Martin periodinane; NMP = N-methylpyrrolidone.
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alcohol afforded ketone 24 in high yield. The final acid-
mediated cyclocondensation of 24 delivered the desired C3h-
symmetrical star-shaped target compound 4 in moderate
yield (10 steps, 6% overall yield).
Molecular Self-Assembly at a Chemically Inert Solid–
Liquid Interface
Scanning tunneling microscopy investigations were per-
formed at the interface between a 1-phenyloctane solution
and the basal plane of highly oriented pyrolytic graphite
(HOPG; for further information, see the Experimental Sec-
tion). The STM experiment with 1 indicates that this com-
pound self-assembles in a structure with hexagonal sym-
metry and two molecules per unit cell (Figure 1). The cen-
tral hole may be less regularly filled with solvent or mole-
cules of 1, which may partially protrude into the superna-
tant solution. In our proposed molecular model, the bright
areas in the STM image, which correspond to high tunnel-
ing currents, provide the positions of the π systems, possibly
including the phenyl rings of the solution.[14] On the one
hand, the dark areas between the molecules designate the
positions of the bulky chlorine atoms, which provide a rela-
tively low tunneling current,[15] similarly to fluorine
atoms.[14,16] On the other hand, the dark areas are due to
interstices that seem to be caused by the electrostatic repul-
sion between the partially charged chlorine atoms. The
counteracting force is provided by the thermodynamically
quite generally favored adsorption of the large and rigid
molecules from an organic solution at the interface with
graphite.[17] In this model, each star interacts multivalently
with three neighbors. The end groups of the stars interact
such that three chlorine atoms surround one nitrogen atom;
this indicates that this interaction is more favorable than
the two chlorine atoms and the nitrogen atom between
them facing the edge of a phenyl ring, for example. The
bulky chloro substituents here cause the distance between
the nitrogen atom and a hydrogen atom of the central core
to be quite large, which leads to only a weak nitrogen–
hydrogen dipole–dipole interaction. Hence, we observed a
different pattern compared to those recently observed in in-
vestigations of D3h-symmetrical compounds also without
alkyl chains but bearing either only nitrogen[7a] or only
iodine[7b] heteroatoms. In the first case, the packing was at-
tributed to significant nitrogen–hydrogen dipole–dipole in-
teractions, which are blocked in our case here by the chlor-
ine atoms; in the second case iodine–iodine bonds were
evoked, which we do not have here.
Figure 1. STM image of D3h-symmetrical compound 1 showing a
hexagonal arrangement and the proposed detailed molecular model
(van der Waals and orbital models are plotted). Unit cell size: a =
(2.98Ϯ0.18) nm,
b = (2.98Ϯ0.18) nm, α = (63Ϯ3)°, A =
(7.30Ϯ0.44) nm2. Us = –0.84 V, It = 21 pA.
The self-assembly behavior of 2 and 3 was studied to
compare the effect of different lengths of alkyl substituents. molecular van der Waals interactions. Therefore, it is not
The obtained STM image of the decyl-substituted com- surprising that the alkyl chains play an important role in
pound 2 and our proposed molecular model are shown in the self-assembly, as also shown in previous studies.[17] The
Figure 2. The D3h-symmetrical star-shaped molecules pack bright areas in Figure 2 indicate the aromatic core and dem-
in a 2D crystalline structure with hexagonal symmetry, onstrate the hexagonal arrangement of six molecules
which obviously differs from the observed hexagonal lattice around a central gap. However, the detected (very low) tun-
of 1. In contrast to 1, the pyridyl moieties of 2 do not inter- neling current indicates the flexibility of the alkyl chains
digitate, whereas its alkyl chains do owing to strong inter- that point to the central hole.
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2D Self-Assembly of 1,3,5-Tris[4-(4-pyridinyl)phenyl]benzene Derivatives
with the determined area of the central hole in the STM
image. Notably, this central molecule may exhibit a higher
rotational mobility, which fits with the smeared-out con-
trast of the central hole. The symmetry of this pattern re-
sembles the packing of bromo-substituted hexa-peri-benzo-
coronenes, which form D3h-symmetric trimers that also
pack hexagonally and leave a central hole that is filled with
a monomer.[19]
Figure 2. STM image of D3h-symmetrical compound 2 showing a
hexagonal arrangement as well as the proposed detailed molecular
model (van der Waals models are plotted). Unit cell size: a =
(4.00Ϯ0.32) nm,
b = (3.93Ϯ0.31) nm, α = (63Ϯ4)°, A =
(14.0Ϯ1.1) nm2. Us = –1.00 V, It = 30 pA.
The STM experiments with dodecyl-substituted com-
pound 3 provided analogous results (Figure 3). The struc-
tural characteristics of the hexagonal arrangement of 3 are
similar to those of 2, but there are slight differences in the
unit cell parameters. A lengthening of the alkyl chains from
C10 in 2 to C12 in 3 leads as expected to a larger unit cell
(14.0 vs. 18.4 nm2). Interestingly, this modification had a
significant effect on the detailed structural appearance, as
the central hexagonal hole exhibits distinct tunneling prob-
ability. We tentatively propose that one more molecule is
incorporated in the 2D structure owing to the larger central
hole. However, the central hole covers an area of only
2.61Ϯ0.18 nm2, which means that the adsorption of the en-
tire molecule is not possible. Hence, we assume that the
alkyl chains protrude out of the 2D crystalline structure
Figure 3. STM image of D3h-symmetrical compound 3 showing a
hexagonal arrangement as well as the proposed detailed molecular
model (van der Waals and orbital models are plotted, the white ar-
rows designate the pyridine end groups). Unit cell size: a =
(4.63Ϯ0.37) nm,
b = (4.64Ϯ0.37) nm, α = (59Ϯ4)°, A =
(18.4Ϯ1.5) nm2. Us = –1.12 V, It = 32 pA.
The reduced symmetry of the C3h-symmetrical pyridine
into the solution, similarly to the dimethyloctanyl side derivative 4 leads to a remarkably different self-assembly
chains of hexa-peri-benzocoronenes, for example.[18] This is behavior. This compound self-assembles in long chains with
supported by the calculated molecular footprint of the aro- two oppositely oriented molecules per unit cell and with
matic core without alkyl chains (2.3 nm2), which fits well chains (lamellae) packed parallel to each other (Figure 4).
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There are two types of interdigitation in the proposed mo- D3h to C3h by using two different moieties (aryl and alkyl)
lecular model. On the one hand, the phenyl moieties inter- at the pyridine ligand.
act strongly to produce an interdigitated aromatic scaffold
along the lamellae, and on the other hand, the alkyl chains
interact through substantial van der Waals interactions. Ap-
Conclusions
parently, both the alkyl chains and the phenyl group play
We have successfully applied our previously reported
an important role in the formation of the specific lamellar
methodology to the synthesis of new star-shaped com-
structure. The latter cause the dark areas parallel to the
pounds with 2,6-disubstituted pyridine units as end groups.
lamellae in the STM image. Nagata and Ogawa reported a
The applied methods are straightforward and flexible and
should be applicable to other compounds of this type. The
similar behavior of C2-symmetrical N,NЈ-dialkylnaphth-
alenediimide derivatives, for which the formed lattices
efficient generation of the central benzene ring by the acid-
change as a function of the alkyl chain length.[20] In our
mediated cyclocondensation of aryl methyl ketone precur-
sors should also allow the preparation of other D3h- and
C3h-symmetrical systems. To realize the lower symmetry, we
system, the alkyl chain lengths do not dominate the self-
assembly as hexagonal structures were determined in the
STM experiments of 2 and 3. This is the first example that
implemented a monochlorination step in our route. The
shows that the self-assembly of star-shaped molecules can
synthesized star-shaped compounds were investigated by
be dramatically changed by reducing their symmetry from
STM measurements and showed remarkably different self-
assembled monolayers at HOPG. We demonstrated that a
reduction of symmetry from D3h to C3h leads to entirely
different behavior. The D3h-symmetrical compounds 1–3
pack in 2D crystalline structures with hexagonal symmetry,
whereas the C3h-symmetrical derivative 4 forms long chains
that are packed parallel to each other. Our systematic study
of substituents effects on self-assembly processes will help
us to understand and predict these phenomena. In addition,
C3-symmetrical compounds with pyridine end groups such
as 1–4 are interesting owing to their ability to form com-
plexes with metal ions on surfaces for investigation of their
influence on aggregation and the effect of multivalency.[21]
Preliminary investigations of the properties of these deriva-
tives are encouraging, and the complex formation is cur-
rently under investigation.
Experimental Section
Scanning Tunneling Microscopy: STM experiments were performed
at room temperature at the interface between a freshly cleaved
highly oriented pyrolytic graphite (HOPG) surface and an almost
saturated solution of the sample in 1-phenyloctane (Aldrich) by
employing a home-made set-up at a scan speed between 10 and
50 lines/s. The STM images were recorded in constant-current
mode (STM height images). After visualization of the HOPG lat-
tice, a drop of the prepared solution was applied to the basal plane
of HOPG. The STM images were corrected with respect to the
hexagonal HOPG lattice underneath by exploiting the SPIP soft-
ware. In this way, the unit cell of the adsorbate crystal could be
defined with a high degree of precision. The implemented space-
filling models are based on standard van der Waals parameters.
The molecular orbitals were calculated with the DMol3 interface of
Accelrys Materials Studio by using the local-density approximation
method and Perdew–Wang correlation.[22]
General Methods for the Syntheses: See Supporting Information.
The multiplicity of complex AAЈXXЈ systems is abbreviated with
d*, and only the largest coupling constant is given.
Figure 4. STM image of C3h-symmetrical compound 4 showing a
Typical Procedure A for Suzuki Coupling Reactions: To a degassed
lamellar arrangement as well as the proposed detailed molecular
solution of halogenated pyridine, K2CO3 (3 equiv.), and boronic
acid (1.5 equiv.) in dioxane (10 mL/mmol) and water (2.5 mL/
mmol) was added Pd(PPh3)4 (5 mol-%). The resulting mixture was
model (van der Waals and orbital models are plotted). Unit cell
size: a = (3.04Ϯ0.24) nm, b = (3.86Ϯ0.30) nm, α = (65Ϯ3)°, A =
(10.9Ϯ0.87) nm2. Us = –1.07 V, It = 43 pA.
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2D Self-Assembly of 1,3,5-Tris[4-(4-pyridinyl)phenyl]benzene Derivatives
1
heated to reflux until complete conversion (TLC control). After
cooling to room temperature and the addition of water, the mixture
was extracted with CH2Cl2. The combined organic layers were
dried with MgSO4, filtered, and concentrated, and the residue was
purified by silica gel chromatography (hexanes/ethyl acetate) to give
the desired Suzuki coupling product.
hexanes/ethyl acetate 95:5). H NMR (500 MHz, CDCl3): δ = 0.87
(t, J = 6.9 Hz, 6 H, 2 CH3), 1.20–1.40 (m, 36 H, 18 CH2), 1.69–
1.77 (m, 4 H, 2 CH2), 2.80 (mc, 4 H, 2 CH2), 3.36 (s, 6 H, OCH3),
5.45 (s, 1 H, OCHO), 7.17 (s, 2 H, Py-H), 7.54 (d*, J = 8.2 Hz, 2 H,
Ar-H), 7.63 (d*, J = 8.2 Hz, 2 H, Ar-H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.1 (q, CH3), 22.7, 29.3, 29.50, 29.54, 29.58, 29.63,
29.64, 29.66, 30.3, 31.9, 38.7 (11 t, CH2), 52.7 (q, OCH3), 102.7,
117.8, 126.9, 127.3 (4 d, OCHO, Py-H, Ar-H), 138.5, 139.1, 148.9,
Typical Procedure B for Cyclocondensation Reactions: To a stirred
solution of aryl methyl ketone derivative in dry EtOH (1 mL/
10 mmol) was added SiCl4 (10 equiv.) at 0 °C. The resulting mixture
was stirred at room temperature overnight and quenched by the
slow addition of water. Filtration of the resulting precipitate af-
forded the expected star-shaped derivative.
162.5 (4 s, 2 Ar, C-4, C-2) ppm. IR (ATR): ν = 2990–2845 (=C–H,
˜
C–H), 1600–1350 (C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for
C38H64NO2 [M + H]+ 566.4932; found 566.4922.
4-(2,6-Didodecylpyridin-4-yl)benzaldehyde (11): TFA (2.0 mL,
26 mmol) was added dropwise to a solution of acetal 9 (230 mg,
0.41 mmol) in CH2Cl2 (5 mL). The mixture was stirred at room
temperature for 2 h and quenched with saturated aqueous
NaHCO3 solution. The organic phase was washed with saturated
aqueous NaHCO3 solution until pH = 7 was reached. The organic
layer was dried with MgSO4, filtered, and concentrated to give al-
dehyde 11 (220 mg, quant.) as a yellow oil. 1H NMR (500 MHz,
CDCl3): δ = 0.87 (t, J = 7.0 Hz, 6 H, 2 CH3), 1.20–1.40 (m, 36 H,
18 CH2), 1.75 (quint, J = 7.7 Hz, 4 H, 2 CH2), 2.84 (mc, 4 H, 2
CH2), 7.19 (s, 2 H, Py-H), 7.78 (d*, J = 8.2 Hz, 2 H, Ar-H), 7.98
(d*, J = 8.2 Hz, 2 H, Ar-H), 10.08 (s, 1 H, CHO) ppm. 13C NMR
(126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7, 29.3, 29.49, 29.53,
29.58, 29.65, 29.65, 29.67, 30.2, 31.9, 38.7 (11 t, CH2), 117.9, 127.8,
130.3 (3 d, Py-H, Ar-H), 136.2, 162.8 (2 s, C-4, C-2), 191.7 (d,
Typical Procedure C for Coupling Reactions with Grignard Rea-
gents. Grignard Formation: To a stirred suspension of magnesium
turnings (10 equiv.) and an iodine crystal in dry Et2O (1 mL/mmol)
was added the corresponding bromoalkane (2.5 equiv.). To initiate
the reaction, it is sometimes necessary to heat the mixture. The
reaction mixture was heated to reflux for 1 h and then cooled to
room temperature. Coupling Reaction: The solution of the Grignard
reagent was added in one portion to a solution of Fe(acac)3
(10 mol-%) and the corresponding chloropyridine derivative in dry
tetrahydrofuran (THF; 10 mL/mmol) and N-methylpyrrolidone
(1 mL/mmol) at 0 °C. The mixture was stirred for 15 min, quenched
by the addition of brine, and extracted with CH2Cl2. The combined
organic layers were dried with MgSO4 and concentrated to dryness.
The residue was purified by silica gel column chromatography (hex-
anes/ethyl acetate) to give the desired compound.
CHO) ppm. IR (ATR): ν = 2955–2845 (=C–H, C–H), 1690 (C=O),
˜
1595–1425 (C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for
C36H58NO [M + H]+ 520.4513; found 520.4507.
4-(2,6-Dichloropyridin-4-yl)benzaldehyde (6): According to general
procedure A, 2,6-dichloro-4-iodopyridine (830 mg, 3.03 mmol), (4-
formylphenyl)boronic acid (459 mg, 3.06 mmol), K2CO3 (1.67 g,
12.1 mmol), and Pd(PPh3)4 (175 mg, 0.15 mmol) in dioxane
(24 mL) and water (8 mL) were heated to reflux for 4 h. After
workup, the crude solid was washed with hexanes to provide the
expected product 6 as a colorless solid (764 mg, quant.). M.p. 160–
164 °C. 1H NMR (400 MHz, CDCl3): δ = 7.51 (s, 2 H, Py-H), 7.76
(d*, J = 8.4 Hz, 2 H, Ar-H), 8.02 (d*, J = 8.4 Hz, 2 H, Ar-H),
10.10 (s, 1 H, CHO) ppm. 13C NMR (126 MHz, CDCl3): δ = 121.0,
127.9, 130.5 (3 d, Py, 2 Ar-H), 137.2, 141.3, 151.4, 152.4 (4 s, 2 Ar,
1-[4-(2,6-Didodecylpyridin-4-yl)phenyl]ethanol (13): A solution of
methylmagnesium bromide (0.50 mL, 1.54 mmol, 3 m in THF) was
added dropwise at 0 °C to a solution of aldehyde 11 (200 mg,
0.38 mmol) in dry THF (8 mL). The mixture was stirred at room
temperature for 1 h and then quenched with water. The THF was
removed under reduced pressure, and the residue was diluted with
CH2Cl2 and washed with water. The combined organic layers were
dried with MgSO4 and concentrated to dryness to give alcohol 13
1
(190 mg, 92%) as a yellow oil. H NMR (500 MHz, CDCl3): δ =
C-2, C-4), 191.3 (d, CHO) ppm. IR (KBr): ν = 3110–2745 (=C–H,
˜
0.87 (t, J = 7.0 Hz, 6 H, 2 CH3), 1.20–1.40 (m, 36 H, 18 CH2), 1.53
(d, J = 6.5 Hz, 3 H, CH3), 1.69–1.76 (m, 4 H, 2 CH2), 2.79 (mc, 4
H, 2 CH2), 4.97 (q, J = 6.5 Hz, 1 H, CHOH), 7.15 (s, 2 H, Py-H),
7.47 (d*, J = 8.2 Hz, 2 H, Ar-H), 7.60 (d*, J = 8.2 Hz, 2 H, Ar-H)
ppm. 13C NMR (126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7 (t,
CH2), 25.3 (q, CH3), 29.3, 29.49, 29.53, 29.57, 29.62, 29.65, 30.3,
31.9, 31.9, 38.6 (10 t, CH2), 69.9 (d, CHOH), 117.7, 125.9, 127.1
(3 d, Py-H, Ar-H), 138.1, 146.5, 148.5, 162.4 (4 s, 2 Ar, C-4, C-2)
C–H), 1710 (C=O), 1610–1360 (C=C, C=N) cm–1.
2,6-Dichloro-4-[4-(dimethoxymethyl)phenyl]pyridine (7): A solution
of aldehyde
6 (200 mg, 0.79 mmol), trimethyl orthoformate
(0.50 mL, 3.97 mmol), and p-toluenesulfonic acid (8 mg, 46 μmol)
in MeOH (10 mL) was stirred at 50 °C for 4 h. The reaction mix-
ture was diluted with Et2O and washed with 1 m aq. NaHCO3 solu-
tion. The combined organic layers were dried with MgSO4, filtered,
and concentrated to afford acetal 7 (230 mg, 97%) as a grey solid.
M.p. 77–79 °C. 1H NMR (500 MHz, CDCl3): δ = 3.29 (s, 6 H,
OCH3), 5.41 (s, 1 H, OCHO), 7.42 (s, 2 H, Py-H), 7.55 (br. s, 4 H,
Ar-H) ppm. 13C NMR (126 MHz, CDCl3): δ = 52.7 (q, OCH3),
102.4, 120.7, 127.0, 127.8 (4 d, OCHO, Py-H, 2 Ar-H), 135.7, 140.4,
ppm. IR (ATR): ν = 3295 (OH), 2960–2850 (=C–H, C–H), 1600–
˜
1365 (C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for C37H62NO
[M + H]+ 536.4826; found 536.4838.
1-[4-(2,6-Didodecylpyridin-4-yl)phenyl]ethanone (15): To a solution
of alcohol 13 (180 mg, 0.34 mmol) in dry CH2Cl2 (10 mL) was
added Dess–Martin periodinane (200 mg, 0.47 mmol), and the
mixture was stirred at room temperature for 2 h. Na2S2O3 (266 mg,
1.68 mmol) and Et2O (5 mL) were added, and the mixture was
stirred for 1 h. After the addition of water, the mixture was ex-
tracted with CH2Cl2. The combined organic layers were dried with
MgSO4, filtered, and concentrated, and the residue was purified by
silica gel chromatography (hexanes/ethyl acetate, 95:5) to give
ketone 15 (141 mg, 79%) as a colorless solid. M.p. 52–53 °C. 1H
NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.0 Hz, 6 H, 2 CH3),
1.20–1.40 (m, 36 H, 18 CH2), 1.74 (mc, 4 H, 2 CH2), 2.65 (s, 3 H,
CH3), 2.82 (mc, 4 H, 2 CH2), 7.18 (s, 2 H, Py-H), 7.71 (d*, J =
151.1, 153.5 (4 s, 2 Ar, C-2, C-4) ppm. IR (KBr): ν = 3075–2885
˜
(=C–H, C–H), 2830 (O–CH3), 1580–1360 (C=C, C=N) cm–1.
HRMS (ESI-TOF): calcd. for C14H14Cl2NO2 [M + H]+ 298.0396;
found 298.0323. C14H13Cl2NO2 (298.2): calcd. C 56.39, H 4.39, N
4.70; found C 56.24, H 4.54, N 4.29.
4-[4-(Dimethoxymethyl)phenyl]-2,6-didodecylpyridine (9): Accord-
ing to general procedure C, Mg (326 mg, 13.4 mmol), 1-bromo-
dodecane (0.80 mL, 3.35 mmol) in Et2O (5 mL), Fe(acac)3 (47 mg,
0.1 mmol), and dichloropyridine derivative 7 (200 mg, 0.67 mmol)
in THF (10 mL) and N-methylpyrrolidone (1 mL) gave 9 (233 mg,
61%) as a yellow oil after purification on silica gel (hexanes to
Eur. J. Org. Chem. 2014, 4985–4992
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4991

D. Trawny, L. Vandromme, J. P. Rabe, H.-U. Reissig
FULL PAPER
8.5 Hz, 2 H, Ar-H), 8.05 (d*, J = 8.5 Hz, 2 H, Ar-H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 14.1 (q, CH3), 22.7 (t, CH2), 26.7
(q, CH3), 29.3, 29.46, 29.48, 29.55, 29.61, 29.62, 29.64, 30.3, 31.9,
38.7 (10 t, CH2), 117.8, 127.3, 128.9 (3 d, Py-H, 2 Ar-H), 136.9,
143.6, 147.5, 162.8, (4 s, 2 Ar, C-4, C-2), 197.6 (s, CO) ppm. IR
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(KBr): ν = 2960–2850 (=C–H, C–H), 1680 (C=O), 1600–1270
˜
(C=C, C=N) cm–1. HRMS (ESI-TOF): calcd. for C37H60NO [M +
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to general procedure B: To a stirred solution of ketone 15 (100 mg,
0.19 mmol) in dry EtOH (1 mL) was added SiCl4 (0.26 mL,
2.25 mmol) at 0 °C. The mixture was warmed overnight to room
temperature and stirred for another 4 d. After the addition of water,
the aqueous phase was extracted with CH2Cl2 to afford the crude
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1.23–1.45 (m, 84 H, 42 CH2), 1.94 (br. s, 12 H, 6 CH2), 3.42 (br. s,
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˜
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Supporting Information (see footnote on the first page of this arti-
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The generous support by the Deutsche Forschungsgemeinschaft
(SFB 765), the Evonik Foundation (PhD fellowship for D. T.), and
Bayer HealthCare is gratefully acknowledged. We thank Susie
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Received: March 3, 2014
Published Online: June 30, 2014
4992
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4985–4992