Organic halogenation chemistry as a vital tool for the construction of functional π-conjugated materials

Article abstract of DOI:10.1055/s-0030-1260086

Recent and ongoing efforts by the Tovar research group to exploit organic halogenation chemistry for the development of complex organic electronic materials are described. Standard synthetic approaches involving free-radical and electrophilic reaction pathways are presented along with strategies that use ionizable protons or triazenes as masking groups for aromatic halides. Forward synthetic processes that highlight the extended chemistry that can be applied to these halogenated substrates to give complex π-conjugated molecules are also discussed. The examples presented are specific to work from the groups laboratories, but the halogenation procedures are sufficiently general to be suitable for use on many other conjugated frameworks. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260086

SPECIAL TOPIC
2387
Organic Halogenation Chemistry as a Vital Tool for the Construction of
Functional p-Conjugated Materials
John D. Tovar*
Department of Chemistry and Department of Materials Science and Engineering, Johns Hopkins University,
3400 North Charles Street (NCB 316), Baltimore, MD 21218, USA
Fax +1(410)5167077; E-mail: tovar@jhu.edu
Received 21 February 2011
syntheses lies the need for rational and controllable
functionalization of precursor building blocks so that the
desired target architectures can be constructed by estab-
lished chemistries. By taking the work of my group as an
Abstract: Recent and ongoing efforts by the Tovar research group
to exploit organic halogenation chemistry for the development of
complex organic electronic materials are described. Standard syn-
thetic approaches involving free-radical and electrophilic reaction
pathways are presented along with strategies that use ionizable pro- example, this short review will highlight some of the more
tons or triazenes as masking groups for aromatic halides. Forward
powerful and generally applicable approaches (‘secret
synthetic processes that highlight the extended chemistry that can
family recipes’) that can be used to halogenate the precur-
be applied to these halogenated substrates to give complex p-conju-
sors that are required for the preparation of cross-coupling
gated molecules are also discussed. The examples presented are
or olefination partners. Although we have not focused on
specific to work from the group’s laboratories, but the halogenation
procedures are sufficiently general to be suitable for use on many
other conjugated frameworks.
the development of methods per se, along the way we
have uncovered some unusual reactivities that will be
highlighted here.
Key words: electrophilic aromatic substitutions, free radicals, ar-
enes, halogenation, conjugation
Our applications of organic halogenation chemistry have
primarily involved radical brominations of benzylic cen-
ters, electrophilic aromatic halogenations of aromatic cen-
ters, and chemical conversions of masked centers. This
review will illustrate these three fundamental pathways
with specific examples from our research in the past five
years that demonstrate both the halogenation chemistry
and the subsequent synthetic manipulations that are per-
mitted by newly installed carbon–halogen bonds.
The halogenation of organic substrates plays a significant
role in many aspects of modern industrial and academic
synthetic chemistry. Halogenation permits the installation
of a functional handle for subsequent chemical manipula-
tion. In this respect, the reactivity of organic iodides, bro-
mides, and, more recently, chlorides1,2 in both saturated
and unsaturated bonding environments permits a wide
range of substitution and cross-coupling reactions. Halo-
genation also permits the tailoring of the size and elec-
tronic structure of a target molecule. In this respect,
organofluorine compounds have come to the forefront.
Through exploitation of the complementary sizes and
vastly different electronegativities of fluorine and hydro-
gen, new ways have been developed for moderating bind-
ing affinities to biological receptors.3,4 The development
of new strategies to achieve chemo- and enantioselective
halogenation of organic substrates continues, justifiably,
to be an active area of chemical research.
Radical bromination. Free-radical bromination at ben-
zylic carbon centers is a simple way to install benzylic
bromide functionality that can be used for a variety of sub-
sequent nucleophilic substitution reactions.5 In our work
on dibenzoborepin frameworks,6,7 we used free-radical
bromination of substituted toluenes such as 1a to prepare
a series of benzylic bromide substrates, such as the bromo
iodo derivative 2a (Scheme 1). This and related benzylic
bromides serve as common precursors for the formation
of the Wittig olefination reactants needed to assemble cis-
stilbenes, such as 3. The dihalide 2a and related com-
pounds were subjected to N-methylmorpholine N-oxide
(NMO)-mediated oxidations to give benzaldehydes such
as 4a, whereas Arbuzov reactions with triphenylphos-
phine nucleophiles gave phosphonium salts such as 5. In
a typical example, compounds 4a and 5 were subsequent-
ly combined in the presence of a base to give the polyha-
logenated stilbene 3 with very high cis selectivity. This
product and related cis-stilbenes were subsequently used
to produce dibenzoborepin frameworks by means of
chemoselective lithiation at the more reactive halide of the
stilbene (R1 in the case of 3). Subsequent trapping by di-
methyltin chloride formed a stannocycle that was subject-
ed to a tin–boron exchange metathesis leading to the
aromatic boron framework. The remaining halogens on
the borepin structure (e.g., where R1 = Br) can be used in
Our research is concerned with all types of p-conjugated
organic electronic materials. In general, the construction
of these materials relies heavily on established methods
for the formation of C–C bonds between unsaturated car-
bon centers (such as palladium- and nickel-catalyzed
cross-coupling reactions) or for the formation of unsatur-
ated alkene or alkyne linkages between aromatic rings
(such as alkene/alkyne metathesis or Wittig/Horner–
Wadsworth–Emmons olefination). At the core of these
SYNTHESIS 2011, No. 15, pp 2387–2391
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260086; Art ID: C21511SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

2388
J. D. Tovar
SPECIAL TOPIC
subsequent syntheses to prepare more elaborate p-conju- treatment with N-iodosuccinimide and mercuration) or
gated molecules and polymers.
the direct use of molecular bromine. In most cases, our
aromatic substrates of choice are thiophene derivatives.
The a-positions of thiophene rings are primed for a variety
of substitution reactions, irrespective of whether they are
present in a conjugated oligomer or in a condensed poly-
cyclic aromatic compound. The most common approach
involves the formal use of molecular bromine (or another
suitable source of ‘Br+’) as an electrophile that is attacked
by an aromatic ring such as 8 to produce a Wheland-type
intermediate such as 9 that undergoes expulsion of hydro-
gen bromide to give an a-bromothiophene such as 10
(Scheme 2). The resulting bromothiophenes are suitable
for synthetic manipulation by a range of palladium cross-
coupling reactions to produce extended p-conjugated
molecules. The use of NBS under conditions that foster
ionic chemistry (such as polar solvents with the exclusion
of light) permits the slow generation of molecular bro-
mine rather than bromide radicals that undergo the free-
radical additions discussed above. In most cases, the lack
of sensitive functional groups on our substrates of interest
allows us to use molecular bromine directly.
Parallel work in our laboratory directed at the syntheses of
oligophenylene vinylene motifs for biomaterials
applications8 used other benzylic bromides (such as 1b) as
precursors of the corresponding phosphonate esters (such
as 6).9 Ester 6 was used to prepare trans-stilbene 7 through
a Horner–Wadsworth–Emmons reaction with the com-
mercially available benzaldehyde 4b.10 Esters of 7 were
saponified and the resulting stilbene diacid was used for
an on-resin dimerization with support-bound oligopeptide
chains that, following cleavage from the solid-phase syn-
thesis resin, gave a self-assembling molecular material ca-
pable of forming well-defined one-dimensional
nanostructures with delocalized electronic properties.
These and other diacid units can be readily incorporated
into a diverse array of peptidic structures with tunable
photophysical and biological activities.
Electrophilic aromatic substitution. Most of our halo-
genation reactions involve classical aromatic substitution
using N-bromosuccinimide (NBS) as a mild source of mo-
lecular bromine.11 Other variants involve iodination (by
R2
R1
Ph3P
DMF
PPh3Br
R2
R2
5
(97% from 2a)
KO-t-Bu
free-radical halogenation
THF, 0 °C
R1
R1
NBS
NMO
R2
R1
R2
R1
R2
R1
O
3 (94% from 4a and 5)
BzOOBz
MeCN, 0 °C
DCE
reflux
Br
4 Å MS
R1
R2
NaOMe
2a (66% from 1a)
2b (not isolated)
4a (90% from 2a)
4b (R1 = H, R2 = CO2Me)
R2
1a (R1 = I, R2 = Br)
1b (R1 = H, R2 = CO2Me)
THF, 0 °C
R1
R2
R1
P(OEt)3
7 (45% from 4b and 6)
P(O)(OEt)2
6 (60% over
2 steps from 1b)
Mes*
B
OMe
...leading to complex
p-electron materials
a borepin-containing
polycyclic aromatic
B
MeO
Mes*
CO2H
O
O
O
H
O
O
O
H
H
H
H
OH
N
N
N
N
N
N
N
H
N
H
HO
N
N
H
H
H
O
O
O
O
O
O
a self-assembling π-electron peptide
CO2H
Scheme 1 Free-radical halogenation as a route to reactants for Wittig (top) or Horner–Wadsworth–Emmons (bottom) olefination reactions,
and representative molecular products available from the resulting stilbene building blocks
Synthesis 2011, No. 15, 2387–2391 © Thieme Stuttgart · New York

SPECIAL TOPIC
Halogenation Strategies in p-Conjugated Molecule Synthesis
2389
resents a situation in which the conformational space
available serves as a ‘protecting group’ without the need
for masking groups on the thienyl moieties or other syn-
thetic interconversions. After the initial chemoselective
bromination, we could cross couple the unsaturated moi-
eties at the newly installed thienyl bromide moieties to
give, for example, the diyne 13; we could then halogenate
the remaining thienyl a-positions to permit further reac-
tions. This technique permitted rapid preparation of com-
plex cruciform-shaped molecular-electronic materials by
fairly simple reaction sequences without the need for pri-
or synthesis of challenging cross-coupling partners.
Br+
– H+
Br
S
H
S
S
Br
H
8
9
10
Scheme 2 Electrophilic halogenation of thiophene
In the course of our efforts to produce photochromic
switching molecules derived from crowded tetrathienyl
benzene core scaffolds, we found an unusual example of
a conformationally driven chemoselective halogenation
among four similarly reactive thiophene a-positions.12
Treatment of the tetrathienylbenzene 11 with four equiv-
alents of molecular bromine led to exhaustive tetrabromi-
nation of the four unsubstituted a-thienyl positions,
whereas treatment with two equivalents of NBS led to
quantitative and gram-scale conversion into the dibro-
mide 12 (Scheme 3). Through a series of model studies
and competition experiments, we determined that the
chemoselectivity was imparted by the conformational
preferences of the core scaffold. This allowed the reactive
thiophene moieties to maintain greater coplanarity with
the central benzene core, resulting in better stabilization
of the arenium intermediate A (Scheme 3) through delo-
calization, as opposed to the inductive influence that di-
rects bromination to the methylthiophene moieties.
Although a fairly specialized example, this selectivity rep-
Conversion of masked substrates. Several protecting or
masking groups have been developed that are useful in
syntheses of halogenated aromatic substrates. By the term
‘masking groups’, I mean functional groups or handles
that must be chemically manipulated and subsequently
unveiled before further chemical reaction. For example,
simple deprotonation of the relatively acidic a-thienyl
protons remaining on 13 removed the masking protons of
the a-carbons, and the resulting unveiled dianion could be
trapped with molecular iodine to give the diiodide 14
(Scheme 3). This is conceptually distinct from the electro-
philic halogenations described above, in that the electro-
phile is attacked by the aromatic nucleus while the C–H
bond is still intact. The intermediate regains its aroma-
ticity through expulsion of the now-acidic proton.
S
S
S
Br
S
S
S
NBS (2 equiv)
DMF (96%)
TIPS
H
S
Pd(PPh3)2Cl2, CuI
TEA, THF, r.t. (90%)
S
S
Br
Br
S
S
S
A
12
11
I
TIPS
TIPS
S
S
1) BuLi
2) I2
S
Pd(PPh3)4, K2CO3
S
S
MeO
B(OH)2
TMEDA, THF
0 °C (86%)
S
S
MeO
S
TIPS
TIPS
THF, H2O, reflux (42%)
14
I
13
OMe
OMe
OMe
OMe
S
O
TIPS
S
S
1) TBAF, THF, MeOH
r.t. (94%)
S
S
2) Pd(PPh3)2Cl2, CuI
S
S
I
SAc
S
S
TIPS
MeO
MeO
O
Et3N, THF, r.t. (54%)
S
MeO
MeO
Scheme 3 A conformational protecting group leads to chemoselective bromination of 11, which undergoes subsequent manipulations to form
cruciform molecular wires. Also shown is another example of aromatic halogenation through direct deprotonation of 13 and subsequent quen-
ching with iodine.
Synthesis 2011, No. 15, 2387–2391 © Thieme Stuttgart · New York

2390
J. D. Tovar
SPECIAL TOPIC
N
N
N
N
N
I
N
N
Pd(PPh3)4
CsF
MeI
120 °C
2
Br
DMF, 80 °C
(29%)
(75%)
N
N
+
I
16
15
Bu3Sn
SnBu3
Scheme 4 Methylation of triazene 15, a ‘masked iodide’
Of course, much clearer examples of masked substrates cross-coupling reactions to give donor–acceptor mole-
have been demonstrated for the halogenation of p-electron cules.19 Our intentions were to exploit the unusual aroma-
materials. We used one such route, triazene decomposi- ticity of this nonbenzenoid ring in polymer electronic
tion, to produce aryl iodides in an early attempt to prepare applications.20,21 We found that the tempered aromatic na-
a borepin scaffold.13 The necessary triazenes, such as that ture of the annulene core can encourage the delocalization
shown in Scheme 4, can be prepared from the correspond- of charge carriers in annulene-based conjugated poly-
ing aryl amines by Sandmeyer-type reactions followed by mers, a subject of our continued research.
trapping of the diazonium species with a dialkyl amine.
Classical methods for halogenation of organic substrates
The triazene functionalities tolerate the conditions for
still offer tremendous scope for the design and syntheses
both lithiation and palladium-catalyzed cross coupling.
of functional and complex new molecules and materials.
After completing the necessary reactions [here, a Stille
Ongoing development of new methods for chemo- and
coupling between a distannyl acetylene and two equiva-
enantioselective halogenation reactions of complex mole-
lents of an (o-bromoaryl)triazene],14 the triazene groups in
cules will provide additional exciting tools for molecular
architects to apply in the course of their work.
15 were removed by treatment with methyl iodide, ulti-
mately yielding the two aryl iodide groups in the diiodo
derivative 16.15 Strategically, this allows retrosynthetic
General. All reaction manipulations were carried out under purified
nitrogen or argon using Schlenk techniques. Degassed THF and
TMEDA were passed through activated alumina columns, and
TMEDA was stored over KOH pellets. BuLi in hexane was titrated
against diphenylacetic acid. Silica gel (32–63 micron) was used for
column chromatography. All other solvents were of reagent grade
and were used as received from Aldrich or Fisher. Representative
synthetic procedures are shown below; spectral details of the prod-
ucts can be found in the primary research reports.
use of the orthogonal bromide and amino functions on the
starting arene core, rather than risking the potential loss in
chemoselectivity with differently halogenated precursors
[e.g. bromo(iodo)benzenes].
Bromination of methano[10]annulene, a two-faced ar-
omatic? This review will close on a mechanistic note. We
have revisited some of the landmark synthetic approaches
developed by Emanuel Vogel for the construction of the
important 1,6-methano[10]annulene ring system (17).16
Like many of the higher annulenes, [10]annulene can be
considered in some regards as a cyclic polyene. Although
it displays many physical properties that are characteristic
of aromatic molecules, it also displays reactivity that is
markedly olefinic. Vogel noted that the bromination
chemistry of 17 involves addition–elimination sequences
leading to the transient intermediate 18, rather than the
typical electrophilic aromatic substitution found for more
conventional aromatic compounds (Scheme 5).17,18 Elim-
ination of hydrogen bromide led to the aromatized bro-
moannulene 19. Neidlein later demonstrated that
brominated annulenes can be subjected to palladium
Radical Bromination: 4-Bromo-1-(bromomethyl)-2-iodoben-
zene (2a); Typical Procedure7
A soln of 4-bromo-2-iodo-1-methylbenzene (3.94 g, 13.3 mmol) in
DCE (19 mL) was stirred at r.t. under N2 in a 50 mL, two-necked,
round-bottom flask. Benzoyl peroxide (164 mg, 0.663 mmol) and
NBS (2.63 g, 14.6 mmol) were added together, and the resulting
mixture was heated to reflux for 5 h. The mixture was then allowed
to cool to r.t. and the resulting precipitates were filtered off and
washed with hexane. The filtrate was dried (MgSO4), filtered, and
concentrated under reduced pressure to provide an orange solid that
was rinsed with cold MeOH to give an off-white solid that was used
without further purification; yield: 3.27 g (8.75 mmol, 66%).
Electrophilic Aromatic Substitution: 1,4-Bis(5-bromo-2-thie-
nyl)-2,5-bis(3-methyl-2-thienyl)benzene (12); Typical
Procedure12
Br
Br
NBS (0.888 g, 4.99 mmol) was added in one portion to a soln of the
tetrathienylbenzene 11 (1.058 g, 2.434 mmol) in CH2Cl2 (240 mL)
and AcOH (80 mL). The mixture was stirred in the dark at r.t. for 7
d, then transferred to a 1 L flask and vigorously stirred with sat. aq
NaHCO3 for 30 min. The organic layer was washed successively
with aq NaHCO3, 2 M aq KOH, and brine, and then dried (MgSO4),
filtered, and concentrated in vacuo. The residue was purified by
chromatography (silica gel, CH2Cl2) to give a tan-colored solid;
yield: 1.383 g (2.334 mmol, 96%).
Br2
H
– HBr
0 °C
CHCl3
–60 °C
Br
19
17
H
18
Scheme 5 Mechanism proposed by Vogel for the addition–elimina-
tion sequence operative during the bromination of 1,6-metha-
no[10]annulene
Synthesis 2011, No. 15, 2387–2391 © Thieme Stuttgart · New York

SPECIAL TOPIC
Halogenation Strategies in p-Conjugated Molecule Synthesis
2391
Quenching of a Thienyl Anion: 1,4-Bis(5-iodo-3-methyl-2-thie-
nyl)-2,5-bis{5-[(triisopropylsilyl)ethynyl]-2-thienyl}benzene
(14); Typical Procedure12
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by syringe in one portion to a soln of diyne 13 (0.190 g, 0.239
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Acknowledgment
Work described in this article was supported by Johns Hopkins Uni-
versity, the National Science Foundation (CAREER, DMR-
0644727), the Petroleum Research Fund (administered by the ACS,
PRF-45738-G7), and the Department of Energy Office of Basic En-
ergy Sciences (DE-SC0004857 peptide nanomaterials). I thank
Anthony Caruso Jr. and Brian D. Wall for assisting in the prepara-
tion of this manuscript.
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Synthesis 2011, No. 15, 2387–2391 © Thieme Stuttgart · New York