Remote aromatic stabilization in radical reactions

Article abstract of DOI:10.1016/j.tetlet.2008.04.009

The rates of free radical reduction of a series of anthracene derivatives and 1-phenyl-4-bromodecane with tributyltin hydride are mediated by the remote aromatic substituent in an apparent through-space interaction. Density functional calculations suggest that this enhancement is not due to direct stabilization of the free radical intermediate, and is likely to be achieved through the interaction of the aromatic moiety with the polarized transition state leading to the intermediate.

Full text of DOI:10.1016/j.tetlet.2008.04.009

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3613–3615
Remote aromatic stabilization in radical reactions
Alfonso Garcia Cabellero, Anna K. Croft *, Stefano M. Nalli
School of Chemistry, University of Wales Bangor, Bangor, Gwynedd LL57 2UW, UK
Received 26 February 2008; revised 17 March 2008; accepted 1 April 2008
Available online 4 April 2008
Abstract
The rates of free radical reduction of a series of anthracene derivatives and 1-phenyl-4-bromodecane with tributyltin hydride are
mediated by the remote aromatic substituent in an apparent through-space interaction. Density functional calculations suggest that
this enhancement is not due to direct stabilization of the free radical intermediate, and is likely to be achieved through the interaction
of the aromatic moiety with the polarized transition state leading to the intermediate.
Ó 2008 Elsevier Ltd. All rights reserved.
Cation-p and, to a lesser extent, anion-p interactions
have been clearly established as having important influ-
ences on the structural stability of biological and designed
macromolecular systems. The influence of these interac-
tions on the reactivity of cation intermediates was dramat-
ically shown in the 1960s with the pioneering experiments
of Cram.1 Since this time, much literature on cation–aro-
matic stabilization,2,3 and growing literature on possible
anion–aromatic interactions4–7 have appeared. The poten-
tial influence of aromatic moieties on radical reactions
has been established for radical chlorination reactions,
where an aromatic solvent effect for free radical chlorina-
tion reactions was first described by Russell in the late
1950s.8–11 Additionally, it has been reported that aromatic
solvents may play a role in mediating the radical polymer-
ization of methyl methacrylate.12 It has been established
that radical cations can be directly stabilized by electron-
rich p-systems.13,14
groups are able to stabilize the transition state of a hydro-
gen abstraction reaction from a benzylic position better
than the corresponding ester. In the case of phenylalanine
derivatives, the correspondinghalogen-abstraction reaction
with tri-butyltin hydride, where an electron-rich centre
forms during the transition state, showed no rate differ-
ence between esters and amides. This is consistent with
the neighbouring group interaction preferentially donating
electron density to the positively polarized transition state
of the hydrogen abstraction.17,18
Here, we report preliminary evidence for remote involve-
ment of an aromatic ring in halogen-abstraction reactions.
We have examined the relative rates of halogen abstraction
by tri-butyltin hydride in standard competitive experiments
for three classes of model systems: a non-aromatic control
1, non-rigid 1-phenyl-4-bromodecane 2 and rigid anthra-
cene derivatives 3–5. DFT calculations have been carried
out on molecules 3–5 and their corresponding radicals.
Anchimeric assistance in radical reactions is quite rare
and reports have mostly been restricted to 1,3 neighbouring
group effects. Recently, it has been reported that the rate of
radical reactions can be influenced through electron dona-
tion by neighbouring groups located 1,4-, 1,5- and 1,6- to
the site of radical formation.15,16 In particular, amido
Br
Br
X
1
X
3 X = Me
4 X = H
Br
5 X = NO
*
2
Corresponding author. Tel.: +44 1248 382375; fax: +44 1248 370528.
E-mail address: a.k.croft@bangor.ac.uk (A. K. Croft).
2
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.009

3614
A. G. Cabellero et al. / Tetrahedron Letters 49 (2008) 3613–3615
The anthracene derivatives 3–5 were selected because of
centre overlapped those of the starting material making it
difficult to monitor accurately the rate of their appearance
in the spectra. Reactions were carried out at least in tripli-
cate with less than 5% variation between replicates. Values
for the relative rates of reaction are reported relative to
standard 1, and are presented in Table 1.
their relative ease of synthesis and rigid geometries, which
hold the putative radical above the aromatic cloud. Related
models have also been successfully used to examine cation–p
interactions.19
Model systems 1–5 were prepared from commercially
available reagents as supplied, without further purification
unless otherwise stated. All reactions that required an inert
atmosphere were carried out under Schlenk conditions
using either dry nitrogen or dry argon as the inert gas
through a standard nitrogen line. The solvents were dis-
tilled and dried by standard methods unless otherwise sta-
ted. 4-Bromodecane 1 was synthesized in 96% yield from
the corresponding commercially-available alcohol, 4-deca-
nol. The synthesis of 1-phenyl-4-bromodecane 2 was via
a two-step process involving initial conversion of 3-bromo-
propyl benzene to the corresponding Grignard reagent
with magnesium turnings in dry ether with iodine catalysis,
followed by treatment with one equivalent of heptanal to
produce 1-phenyl-4-decanol in 77% yield. Following purifi-
cation by column chromatography in 50:50 petrol ether/
dimethyl ether, this alcohol was treated with two equiva-
lents of triphenylphosphine and two equivalents of carbon
tetrabromide to afford derivative 2 in 95% yield.
The relative rates of reaction of derivatives 1–5 reflect the
relative rates of formation of the corresponding radicals, as
bromine abstraction by the tributyltin radical is the first
committing step in the reduction. The large differences in
the relative rates of reaction for compounds 3–5 are not,
however, reflected by the stabilities of the corresponding
radicals 6–8. This was confirmed through the calculation
of the radical stabilization energies (RSEs) for radicals 6–
8 using density functional theory (DFT) and ab initio
methods. Geometries were optimized for each molecule 3–
8 at the B3LYP/6-31G(d) level, with single point energies
at the RMP2/6-31G(d) level. The use of restricted MP2
with DFT geometries has been shown to provide reliable
energies for large radical systems.22–24 The corresponding
RSEs are presented in Table 2.
Whilst there is a very slight variation in the RSE values
consistent with the electronic nature of the substituent rel-
ative to an electron deficient radical, the direct stabilization
afforded by the aromatic ring is virtually zero. This is con-
firmed by both theoretical methods. Therefore, the relative
reactivity cannot be accounted for by direct stabilization
of the intermediate radical. The relative rates appear,
however, to be determined by the electron-withdrawing
and electron-donating abilities of the aryl substituents,
indicating a through-space interaction. Furthermore, for
compounds 3–5, the relative rates follow a Hammett rela-
tionship with a correlation coefficient (R2) of 0.9953 and
a positive q value of 0.92. This is consistent with the reac-
tion proceeding through a transition state with a weak neg-
ative charge (Fig. 1), as has been previously proposed for
tributyltin hydride reactions.25
The unsubstituted derivative 4 was prepared in three
steps through a modification of literature methodology.20
Firstly, Diels-Alder reaction of anthracene with an equiva-
lent each of ethyl acrylate and AlCl3 afforded the 9,10-
bridged ester after 24 h in 88% yield, which was reduced
with 2.5 equiv of LiAlH4 to yield the corresponding alcohol
in 80% yield. This alcohol was transformed with two
equivalents each of triphenylphosphine and carbon tetra-
bromide to give compound 4 in 89% yield. Nitro-derivative
5 was synthesized as a separable mixture of regioisomers in
92% yield overall of dinitrated material from 4 by treat-
ment with 8.5 equiv of trifluoroacetic anhydride and 2.5
equiv of ammonium nitrate. Chromatography afforded
the required 2,6-derivative 5 in 39% yield and the corre-
sponding 2,7-derivative in 54% yield. The dimethyl ana-
logue 3 was prepared from 2,6-dimethylanthraquinone,
which was reduced to the corresponding anthracene in
alkaline solution with zinc dust under reflux. The subse-
quent preparation of the brominated anthracene derivative
3 then followed the same general procedure outlined for 4,
in 34% overall yield. Detailed descriptions of the synthetic
procedures are available in the Supplementary data.
Relative rates of reaction of bromides 1–5 were obtained
through standard competitive reduction with tributyltin
hydride (see Supplementary data), by measuring the rela-
tive rates of consumption of the starting materials using
The anthracene models possess a restricted geometry,
ensuring that interaction takes place. It is interesting to
note, however, that the unrestricted aromatic derivative
2, did show a slightly larger rate relative to 1. As the com-
petitive reactions ensure that each compound experiences
Table 1
Rates of reaction of compounds 2–5, relative to that of alkyl bromide 1
Compound
X
krel (Bu3SnH)
RSDa (%)
1
2
3
4
5
a
n/a
H
CH3
H
1b
—
1.24 0.05c
1.12 0.05d
1.39 0.04d
7.98 0.28d
4.9
3.7
4.0
4.0
1
NO2
either H NMR spectroscopy or GC/MS. In the case of
1
Relative standard deviation.
Assigned as unity.
Data obtained via GC/MS. All other relative rates obtained by
the rates calculated from H NMR, the disappearance of
b
c
the CHBr signals at d 4.06 ppm for compounds 1 and 2,
and at ca. d 2.80 and 3.10 for compounds 3–5 were mea-
sured relative to 0.2 equiv of mesitylene, which was utilized
as an internal standard. The formation of products was not
1H NMR.
d
It is worth noting that these are rates of reaction at a 1° centre, whereas
rates for 1 and 2 are at 2° centers. The estimated rate increase for Bu3Sn
1
for a 2° centre over a 1° centre is 2.9 fold.21
monitored, as the H NMR signals relating to the reduced

A. G. Cabellero et al. / Tetrahedron Letters 49 (2008) 3613–3615
3615
Table 2
Acknowledgement
Radical stabilization energies (RSEs) of the radicals 6–8 in kJ molÀ1
relative to radical 7
,
This research was supported by the EPSRC (Grant
Number GR/R51131/01) and the European Social Fund.
We would like to thank Dr. Ian R. Butler for extensive
useful discussions.
X
X
Supplementary data
6 X = Me
7 X = H
8 X = NO
2
Full synthetic details, methodology for the competitive
experiments, and calculated geometries for molecules 3–8
are available. Supplementary data associated with this
article can be found, in the online version, at doi:10.
1016/j.tetlet.2008.04.009.
Radical
X
B3LYP/6-31G(d)
RMP2/6-31G(d)
6
7
8
CH3
H
NO2
0.16
0.00
À0.41
0.16
0.00
À0.32
References and notes
δ
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