Conformation as a protecting group: A regioselective aromatic bromination en route to complex π-electron systems

Article abstract of DOI:10.1021/ol801828n

(Chemical Equation Presented) A new strategy to achieve regioselective functionalization of a sterically congested aromatic system driven by conformational demands is described. Electrophilic substitution occurs at the more planarizable subunit without undesired chemistry at mutually reactive sites and without the need for protecting or masking groups that must be manipulated later. Model studies are described to understand this selectivity, and possibilities for the construction of orthogonal, differentially substituted π-systems of relevance for molecular electronics are demonstrated.

Full text of DOI:10.1021/ol801828n

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4323-4326
Conformation as a Protecting Group: A
Regioselective Aromatic Bromination En
Route to Complex π-Electron Systems
Daryl A. Guthrie and John D. Tovar*
Department of Chemistry, Johns Hopkins UniVersity, Baltimore, Maryland 21218
toVar@jhu.edu
Received August 6, 2008
ABSTRACT
A new strategy to achieve regioselective functionalization of a sterically congested aromatic system driven by conformational demands is
described. Electrophilic substitution occurs at the more planarizable subunit without undesired chemistry at mutually reactive sites and without
the need for protecting or masking groups that must be manipulated later. Model studies are described to understand this selectivity, and
possibilities for the construction of orthogonal, differentially substituted π-systems of relevance for molecular electronics are demonstrated.
The conformational dynamics of congested oligoaromatic
molecules have been a subject of intense research for several
decades.1 Steric bulk positioned ortho to arene-arene
linkages has pronounced effects on the available macromo-
lecular conformational space. In the most extreme of cases,
this leads to atropisomerism allowing for the separation and
isolation of distinct conformations at room temperature. More
commonly, conformation has marked impacts on reactivity,
such as the dramatic rate differences found during the course
of several transformations of cyclohexanes possessing reac-
tive axial or equatorial substituents.2 We report here our
studies of a crowded aromatic system that bears mutually
reactive sites yet whose conformation allows for these sites
to be addressed selectively and in a stepwise manner rather
than reacting simultaneously but at different rates, in effect
a conformationally controlled and protecting-group-free
regioselective bromination. We present model systems to
understand the selectivity and then apply this transformation
to the syntheses of conformationally distinct thioacetate-
functionalized π-conjugated systems of relevance for organic
electronics.
The synthesis of elaborate organic electronic materials
poses a frustrating bottleneck in the pursuit of fundamental
investigations or commercial exploitations. Palladium-
catalyzed cross-coupling chemistry has risen to this challenge
as witnessed by π-conjugated cruciform architectures and
other types of cross-conjugated systems.3 In some cases,
these molecules are built by joining two complex subunits
at a late stage in the synthetic execution; unfortunately, the
requisite cross-coupling partners are not routinely available
on the scales of their simpler commercial counterparts.
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10.1021/ol801828n CCC: $40.75
Published on Web 09/09/2008
2008 American Chemical Society

Iterative construction of π-conjugated architectures via
selective masking and unveiling of reactive functional groups
has yielded many complex structures built from simpler
components.4 Equally important is the development of new
chemistry that minimizes reliance on protecting group
manipulation to selectively and in a stepwise manner
functionalize particular sites of π-conjugated systems in the
presence of multiple mutually reactive sites.
Sterically congested 1 was designed as an electrochemical
precursor to porous conducting polymers since the four
o-thiophenes cannot adopt completely coplanar conforma-
tions. It bears two distinct p-di-2-thienylbenzene (DTB)
subunits with reactive R-thienyl positions indicated by the
carbons attached to HR (DTB-R) and Hꢀ (DTB-ꢀ). We could
not determine the prevalent connectivity of electrochemically
prepared polymers derived from 1 given the lack of structural
detail afforded by cyclic voltammetry (CV). We conjectured
that the methyl groups should enforce a more twisted
π-system in the DTB-ꢀ fragment, thereby biasing polymer-
ization through the more easily planarized DTB-R fragment
(boldened in 1). On the other hand, the slightly electron-
donating methyl groups would favor oxidation and subse-
quent reactivity through the DTB-ꢀ fragment with or without
the need to engage the entire DTB π-system.
intermediates (such as B) given the potential for steric
clashing between the thienyl methyl groups and the phe-
nylene ring protons if forced into coplanarity. However,
treatment of 1 with 4.2 equiv of Br2 (route B) provided
tetrabromide 3 quantitatively. The fact that both DTB
pathways reacted set the stage for the selective and stepwise
construction of differently substituted π-conjugated systems
built from the core scaffold 1. Before proceeding, we sought
to understand the origins of this unusual selectivity.
Thiophenes readily brominate at the R-positions, and the
slightly electron-donating methyl substituent would suggest
enhanced reactivity at the Hꢀ carbons of DTB-ꢀ in the
absence of any directing stereoelectronic effects. We prepared
models to dissect or block the DTB pathways present in 1
(Figure 1) using routine Stille coupling to install the
Figure 1. Model DTB pathways and their calculated (B3LYP/6-
31G*, Spartan) thiophene-phenylene dihedral angles determined
about the bonds labeled by R or ꢀ.
Scheme 1. Regioselective (Route A) and Exhaustive (Route B)
Bromination of a Crowded Aromatic (Top) and Possible
Reaction Intermediates (Bottom)
individual thiophenes. Models 4 and 5 eliminated any
cofacial influences while maintaining the presumably reactive
oligoaromatic DTB π-system. Models 6 and 7 were prepared
to examine the reactivity of DTB-R and DTB-ꢀ in the
presence of cofacial thiophenes that have been rendered
unreactive due to the R-methyl groups.
Comparative reactivity studies were conducted with the
two sets of model compounds. Both 4 and 5 were separately
treated with NBS to provide near-quantitative conversions
to their respective R,R′-dibromides (HRfBr). Competition
experiments with equimolar ratios of 4 and 5 led to
essentially equimolar consumption when applying either
route A or route B. While 6 was consumed over the course
of 3 days under route A conditions to converge on what we
also assign as the R,R′-dibromide (HRfBr), 7 provided a
complex and undecipherable mixture of products. This is due
to apparent reactivity elsewhere within 7 such as along the
R-methyl fragment shown in bold. Although interpretation
of the competition experiments between 6 and 7 was
precluded by the lack of clear NMR handles that could be
resolved and assigned to products resulting from bromination
at the carbon bearing HR (6) or Hꢀ (7), over the course of 1
week, 6 was consumed in greater amounts when reacted
competitively with 7.
As the intermediates formed during electrophilic aromatic
substitution resemble those from anodic electropolymeriza-
tion, we examined the reactivity of 1 with brominating agents
(structures A and B represent possible brominated intermedi-
ates). Initial experiments indicated a strong preference (ca.
80-90%) for the dibromide 2 corresponding to bromination
at the carbon formerly bearing HR: the optimized conditions
(route A) yielded 2 quantitatively and on a gram-scale.
Reaction through DTB-ꢀ might require higher energy planar
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Soc. 1992, 114, 2273–2274. (b) Schumm, J. S.; Pearson, D. L.; Tour, J. M.
Angew. Chem., Int. Ed. Engl. 1994, 33, 1360–1363. (c) Liess, P.; Hensel,
V.; Schlu¨ter, A.-D. Liebigs Ann. 1996, 1037–1040. (d) Bell, M. L.; Chiechi,
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These results at first glance may seem to indicate that both
DTB pathways are viable reaction partners during the slow
generation of bromine in route A. However, they are
consistent with the reactivity found for 1 after inspection of
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Org. Lett., Vol. 10, No. 19, 2008

the relevant dihedral angles existing among neighboring
thiophene and benzene units (Figure 1, right). Despite the
difference in calculated gas-phase (B3LYP/6-31G*) dihedral
angles among the planes of the arenes in 5 (43°) relative to
4 (25°), the thiophene nuclei of both dissected DTB pathways
underwent comparable electrophilic aromatic substitution.
The calculated dihedral of 6 was 49°, rendering it slowly
reactive under the conditions of route A, while the 61°
dihedral for 7 shut down a clean reaction at Hꢀ. Given that
1 holds dihedral angles within the DTB-R and DTB-ꢀ
segments at 38° and 61°, respectively, there must exist a
transition between 50°-60° at which point the bromination
becomes less favorable (vide infra).
reactivity for 7 and the selectivity observed in the bromi-
nation of the DTB-R pathway in 1. The 61° dihedral within
DTB-ꢀ renders its ionization potential high enough to drive
reactivity to the more coplanar DTB-R π-system of 1 yet
not high enough to shut down reactivity under more
aggressive conditions. This subtle energy difference is
powerful enough to take advantage of synthetically as further
described below.
Palladium cross-coupling efficiently diversified the elec-
tronics of the DTB-R pathway of dibromide 2 via arylation
(Stille, 8a; Suzuki, 8d) and alkynylation (Sonogashira, 8b,c).
Subsequently, a diverse scope of reaction chemistries listed
in Table 1 was employed for additional manipulation at the
Trends in reactivity were mirrored in electronics. The first
CV sweep of 4 and 5 revealed essentially identical onsets
of oxidation (0.95 V), although the more complex behavior
for 5 may reflect inductive perturbations of the methyl groups
or differences in diffusion to the working electrode (Figure
2A). The onset for 1 was more positiVe than for 4, but the
Table 1. Diversification of the DTB-ꢀ Pathwaya
a Reagents and conditions: (A) NBS, DMF, rt; (B) (i) n-BuLi (3 equiv),
THF, TMEDA, 0 °C, (ii) I2, 0 °C to rt; (C) same as (B) but no TMEDA;
(D) (i) Hg(OAc)2, CH2Cl2/AcOH (95:5), rt; (ii) I2. b Yield from NMR
analysis of mixtures with inseparable monohalogenated impurities.
Figure 2. (A) CV and (B) UV-vis for 1 (ss), 4 (---) and 5 (···).
CV conditions: 100 mV/s at a 2 mm2 Pt button, 0.2 mM monomer
in 0.1 M n-Bu4PF6/CH2Cl2. UV-vis conditions: CHCl3.
carbon bearing Hꢀ such as electrophilic halogenation (9a,d)
and direct R-thienyl lithiation (9b,c). The conversion of 8a
to 9a using NBS was more the exception that the rule: most
other substrates provided complex reaction mixtures after
treatment with NBS or molecular bromine. Indeed, these
reaction conditions were not easily generalized for other
substrates thereby requiring fine-tuning of specific conditions
on a case-by-case basis. Although we focused our efforts
on thienyl halides for palladium cross-coupling, the orga-
nolithium intermediates prepared in situ could be trapped in
principle by a variety of other electrophiles to generate
Grignard reagents, silanes, aldehydes, etc.
After installing the reactive handles, we prepared mol-
ecules designed to assemble on electronically relevant
surfaces (Scheme 2). It is important to recognize that the
sequences from 2 utilize fairly routine transformations and
smaller cross-coupling partners.7 From 9b, a Suzuki, pro-
tiodesilylation and Sonogashira sequence yielded 10 while
Sonogashira coupling on 9d yielded 11. The conformation
imposed on the π-systems spanning the two distinct thio-
acetate linkage pathways was a key design element. The more
potentials of peak anodic activity (Ep,a) for 1 and 4 were
identical. The UV-vis of 1 revealed a bimodal signature
with peak absorptions at 290 and 322 nm, while 4 had a
λ
max at 324 nm and 5 had a λmax at 305 nm (Figure 2B). The
lower energy λmax of 4 (compared to 5) implies a longer
conjugation path as expected for a system that should be
easier to planarize given the lack of steric clashing from the
methyl groups. The lower energy absorption of 1 closely
matched that of 4.
These data suggest that the methylthiophenes play a steric
role to dictate solution conformational preferences and
subsequent reactivity differences among the two DTB
segments, as opposed to an electronic influence stemming
from the cofacially disposed o-thiophenes of 1.5 Oligoth-
iophene ionization potentials increase with the torsion angle
between repeat units, even more sharply at angles greater
than 40°.6 This rationalizes the indiscriminate reactivity of
4 and 5 in competition experiments, the lack of clean
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Org. Lett., Vol. 10, No. 19, 2008
4325

Scheme 2
.
Synthesis of Conformationally Distinct Cruciform
Molecules 10 and 11
Figure 3. Electronic properties of 10 (ss) and 11 (---). Conditions
for UV-vis (A) and CV (B) are as detailed in Figure 2.
Fluorescence excitation at 390 nm.
at the single molecule level. We are currently exploring the
molecular properties of these and related molecules.
In conclusion, we report a highly selective functionaliza-
tion strategy that relies upon the subtle conformational
dynamics of a densely substituted benzene core. Unlike most
conformational effects on reactivity that are manifested in
rate differences among competing conformers, we see here
how conformer energetics effectively protect one site from
engaging an electrophile but do not completely prohibit it.
As both DTB pathways are mutually reactive, this stereo-
electronic bias allows us to address the two pathways
stepwise without the need for masking or blocking groups
that must be unveiled later. Standard manipulations with
readily available reagents can rapidly diversify the simple
core scaffold to generate electronic structures that otherwise
would require synthetically complex cross-coupling partners.
This approach offers unusual molecules whose electronic
properties may be modulated through both macromolecular
conformation and the electronics of their π topologies.
planarizable (boldened) pathway spans the two sulfur anchors
in 10 while in 11 it does not. The dimethoxyphenyl units
were employed only to facilitate chromatography. The
separation of minor side products resulting from incomplete
conversion on more nonpolar substrates proved problematic,
but they could be carried through additional synthetic
transformations and removed at a later stage. The calculated
HOMO and LUMO orbitals for 10 and 11 show clear
differences in spatial distrubution due to the conformational
perturbation imposed on the cruciform π-system. These
densities should prove easily tunable in practice through the
inclusion of different substituents in lieu of the dimethoxy-
benzene moieties.
Acknowledgment. We thank Johns Hopkins University
and the National Science Foundation (CAREER, DMR-
0644727) for generous and continued support.
Experimentally, this conformational bias perturbed the
optical properties and the redox behavior of 10 and 11. The
relative oscillator strengths of the lowest energy transitions
were altered, and the relative luminescence quantum yield
of 10 was reduced by 55% compared to 11 (Figure 3A).
The anodic behavior for 10 was split into two defined redox
processes, while 11 displayed a single redox wave of greater
intensity (Figure 3B). Orbital density, π-conjugated backbone
conformation and through-space interaction also affect charge
transport in molecular electronics.8 The approach described
here will enable the rapid preparation and evaluation of a
spectrum of complex molecular electronic materials relevant
for a more detailed understanding of transport phenomena
Supporting Information Available: Monomer synthetic
schemes, experimental procedures, and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL801828N
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