Reactivity of benzyl radicals: The trapping of primary, secondary and tertiary benzyl radicals with heterocyclic bases

Article abstract of DOI:10.1016/j.jphotochem.2010.05.026

A photochemical benzylation of protonated quinolines was realized by single electron transfer (SET) to the excited state of the quinoline from the aromatic reactant. The benzylated product is formed by cross-coupling between the benzyl radical and the heterocyclic radical when they are in close proximity to one another. This allows the formation of products which are, to the best of our knowledge, unaccessible in other ways and which have now been obtained for the first time.

Full text of DOI:10.1016/j.jphotochem.2010.05.026

Journal of Photochemistry and Photobiology A: Chemistry 214 (2010) 112–114
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Chemistry
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Short note
Reactivity of benzyl radicals: The trapping of primary, secondary and tertiary
benzyl radicals with heterocyclic bases
Luigi Brivioa, Tullio Caronnaa,∗, Francesca Fontanaa, Cristian Gambarottib, Andrea Meleb,c
,
Isabella Natali Soraa, Carlo Puntab, Francesco Recuperob
a Dipartimento di Ingegneria Industriale, Università di Bergamo, viale Marconi 5, 24044 Dalmine, BG, Italy
b Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via L. Mancinelli 7, 20131 Milano, Italy
c CNR-ICRM Istituto di Chimica del Riconoscimento Molecolare, via L. Mancinelli 7, 20131 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2010
Received in revised form 27 May 2010
Accepted 31 May 2010
Available online 8 June 2010
A photochemical benzylation of protonated quinolines was realized by single electron transfer (SET) to
the excited state of the quinoline from the aromatic reactant. The benzylated product is formed by cross-
coupling between the benzyl radical and the heterocyclic radical when they are in close proximity to one
another. This allows the formation of products which are, to the best of our knowledge, unaccessible in
other ways and which have now been obtained for the first time.
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Benzyl radicals
PhotoSET
Benzylquinolines
1. Introduction
umn, 0.25 mm i.d., 0.25 ␮m film thickness and a MS 5973N mass
spectrometer detector.
A recent paper devoted to the determination of the oxidation
potentials of a series of substituted toluenes and biphenyls evi-
denced the possibility of an electron transfer from alkylbenzenes
to excited N-methylquinolinium ions [1]. Since in the course of
our research on the photochemical reactivity of quinolines [2]
interesting reactions were obtained with alkylbenzenes, the above
cited paper prompted us to undertake a rationalization of these
results.
1H NMR analyses were performed with a Bruker Advance 500
spectrometer operating at proton resonance frequency of 500 MHz;
the products were dissolved in a suitable deuterated solvent and
TMS was added as internal reference.
2.2. Photochemical reactions
To a solution of the selected base (20 mmol), dissolved in
acetonitrile (100 mL) in a Pyrex vessel and protonated with p-
toluensulfonic acid (100 mmol), the benzyl derivative (200 mmol)
and 30% aqueous hydrogen peroxide (120 mmol) were added. The
solution was stirred with a magnetic stirrer in open air and irradi-
ated for 16 h at 366 nm. At the end of the irradiation the solution
was treated with an aqueous solution of FeSO4 to destroy the excess
of hydrogen peroxide and of any organic peroxide that may have
formed during the irradiation. Acetonitrile was removed under vac-
uum, the remaining water solution was alkalinized and extracted
with CH2Cl2. The solvent was dried and the organic solution was
analysed via GC–MS; the products were separated via column chro-
matography on silica gel Si 60 40–63 ␮m with n-hexane:ethyl
acetate (80:20) as eluent.
2. Experimental
2.1. Reagents, apparatus and methods
All the reagents and solvents were purchased by Sigma–Aldrich
and were used as received.
The solutions were irradiated through Pyrex glassware in a Ray-
onet RPR-100 reactor, equipped with 16 interchangeable lamps,
selectively emitting at 366 nm, and an internal merry-go-round
apparatus for the homogeneous exposure of the samples to light.
GC–MS analyses were performed with an Agilent 6890 series
gas-chromatograph equipped with a HP-5 MS 30 m capillary col-
2 benzyllepidine (4a) [3] and 4-benzylquinaldine (5a) [4] are
known products.
∗
2-(1-Phenylethyl)-lepidine (4b): oil, ms 247 (M+), 246, 232, 217;
1H NMR: 1.79(d, 3H), 2.60 (s, 3H), 4.47 (q, 1H), 7.04 (s, 1H), 7.20 (t,
Corresponding author. Tel.: +39 0352052322; fax: +39 035562779.
E-mail address: tullio.caronna@unibg.it (T. Caronna).
1010-6030/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jphotochem.2010.05.026

L. Brivio et al. / Journal of Photochemistry and Photobiology A: Chemistry 214 (2010) 112–114
113
Scheme 1.
1H), 7.30 (t, 2H) 7.35 (d, 2H), 7.51 (t, 1H), 7.68 (t, 1H), 7.92 (d, 1H),
8.12 (1H); IR (nm): 2924, 2853, 2360, 2342, 1734, 1653, 1601, 1559,
1541, 1508, 1456, 1375, 1229, 758, 699.
4-(1-Methyl,1-phenylethyl)-quinaldine (5c): ms: 261 (M+), 246,
231. The low yields of this product were not sufficient to obtain a
clean sample for recording good quality 1H NMR and IR spectra.
4-(1-Phenylethyl)-quinaldine (5b): oil, ms 247 (M+), 232, 217;
1H NMR: 1.80 (d, 2H), 2.75 (s, 3H), 4.85 (q, 1H), 7.22 (m, 3H), 7.30
(m, 1H), 7.48 (m, 1H), 7.63 (t, 1H), 7.86 (t, 1H), 7.99 (d, 1H), 8.18
(d, 1H), 8.15 (d, 1H); IR (nm): 2994, 2853, 2360, 1734, 1600, 1508,
1457, 1376, 1233, 761, 701.
3. Results and discussion
In the reactions under investigation, acetonitrile solutions of
toluene (1a), ethylbenzene (1b) or cumene (1c) were irradiated
with 366 nm UV light in the presence of the protonated bases lep-
idine (2) or quinaldine (3) with the purpose of generating benzyl
radicals by SET from the excited protonated heteroaromatic base,
and then trapping these radicals by using the heteroaromatic base
itself as spin trap (Scheme 1) [5].
2-(1-Methyl,1-phenylethyl)-lepidine (4c): oil, ms: 261(M+),
260, 246, 231; 1H NMR:1.88 (s,6H), 2.52 (s, 3H), 6.93, (s,1H), 7.20
(m,1H), 7.30 (m,4H), 7.53 (t, 1H), 7.70 (t,1H), 7.94 (d,1H), 8.15
(d,1H); IR (nm): 2924, 2853, 1731, 1603, 1560, 1494, 1448, 1377,
1261, 1095, 1030, 759, 699,569.
Scheme 2.

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L. Brivio et al. / Journal of Photochemistry and Photobiology A: Chemistry 214 (2010) 112–114
Table 1
In the literature concerning benzyl radical attack onto het-
Yields of the benzylation products.
eroaromatic bases, [6] oxidation and dimerization products of the
benzyl radical are usually detected as by-products. In these cases,
however, the benzyl radical is generated in the presence of the
protonated heteroaromatic bases by an independent hydrogen
abstraction system, such as e.g. a peroxide/metal ion redox chain.
Therefore, it must diffuse in the medium to meet the heteroaro-
matic substrate; besides, the attack is highly reversible due to the
relative stabilization of benzyl radicals.
Heterocyclic base
(Product) Yield %
(1a)
(1b)
(1c)
(2)
(3)
(4a)2
(5a)22
(4b)8
(5b)18
(4c)1a
(5c)6
a
Ref. [6].
The tertiary benzyl substituent has an advantage over the simple
benzyl, in that products such as 4c and 5c cannot undergo benzylic
oxidation. The yields relative to all the benzyl derivatives 4a–c and
5a–c are reported in Table 1.
Besides the above discussed intrinsic difficulties connected with
attack of the cumyl radical, it was particularly surprising to find
out even a small quantity of product 5c, since cross-dimerisation of
tertiary radicals in position 4 of quinaldine is usually not observed,
probably due to steric hindrance by the hydrogen atom in position
5. [10] Furthermore, even in radical attack, substitution by tertiary
radicals is never observed in that position [11]. This reaction could
then be of interest from a synthetic standpoint; work is in progress
in order to try to improve the yields.
Under the conditions employed in this work, (see Section 2)
in the first runs with excess H2O2 no dimer was detected. This
was ascribed to the fact that the two radicals are formed simul-
taneously and in close proximity by SET (Scheme 2), so that the
reaction should not, in this case, be described as an attack of a free
radical onto a protonated heteroaromatic base, to give an interme-
diate radical, but as a cross-dimerization of two radicals to give a
paired electron intermediate, which is then rearomatized by H2O2
oxidation to give the benzylated product.
Therefore, since there is no diffusion of benzyl radicals in solu-
tion, as long as the oxidation of intermediate (6) (Scheme 2) is
efficient, the dimer will not be formed.
Due to its relatively low stability, it is reasonable to consider the
possibility that the non-aromatic intermediate (6) may revert back
to the two parent radicals if it does not undergo immediate oxi-
dation. As the concentration of the oxidant gets lower during the
course of the process the benzyl radical could actually be regener-
ated from (6) by C–C bond breaking, then diffuse in solution and
dimerize to a bibenzyl by-product. To verify this hypothesis, some
reactions were realized at lower amount of hydrogen peroxide.
Indeed, the formation of the dibenzyl was detected in these
cases, and it is interesting to compare the molar ratios benzylhete-
rocycle/bibenzyl with the corresponding ratios found by Minisci
under free-radical conditions [6]. In the case of lepidine we found
0.8 (reported 1.2) and for quinaldine we found 0.7 (reported. 0.13).
The differences among the two processes are not surprising in view
of the lower reversibility of the reaction described here, compared
to the Minisci one, whose intermediate is a radical species, while
intermediate (6) is not.
The benzylquinoline moiety may be found in the structure of
naturally occurring alkaloids, widely studied for their biological
properties, e.g. antimalarial activity [7,8]. Considering this, the
described reaction may provide a synthetic strategy bringing, in
just one step, to benzylated heteroaromatic bases, while known
ionic processes require several steps [9]. Besides, this benzylation
takes place not only with toluene but also with ethylbenzene and
cumene, yielding products with a secondary and respectively ter-
tiary benzyl substituent. These products, 4b, 4c and 5b, 5c, were
never before described, to the best of our knowledge, probably
owing to the difficulty of both ionic and radical attack of such a
hindered and stabilized moiety, together with the ease of subse-
quent benzylic oxidation. This side process would be even more
easy for a doubly benzylic position, so that such benzylated prod-
ucts would be quite labile even in mildly oxidizing environments.
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