Full text of DOI:10.1016/S0040-4039(99)02053-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 229–233
Mechanistic duality of the side-chain substitution in electrophilic
aromatic nitration. Unexpected large difference in deuterium
isotope effect kH/kD between the side-chain nitration and
nitrooxylation of deuterated p-xylenes
Nobuaki Nonoyama, Masao Iwaya and Hitomi Suzuki ∗
Department of Chemistry, School of Science, Kwansei Gakuin University, Uegahara 1-1-155, Nishinomiya 662-8501, Japan
Received 17 September 1999; revised 25 October 1999; accepted 29 October 1999
Abstract
A large difference in deuterium kinetic isotope effect observed between the side-chain nitration and nitro-
oxylation of deuterated p-xylenes, 1,4-(CH3)(CD3)C6H4 and 1,4-(CD3)2C6D4, suggests the operation of different
mechanisms for these two types of side-chain substitution. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: nitration; mechanisms; isotope effects; nitrogen oxides; nitrous acid derivatives.
When treated with nitrating agent, polymethylated benzenes in which at least one pair of methyl groups
exists in para relationship often undergo side-chain substitution in parallel with ring nitration, affording
arylnitromethane and arylmethyl nitrate as important byproducts.1 Mechanistic aspects of these non-
conventional reactions have been subject to much discussion, and opinions among researchers are still
far from consensus.2 Some proposed the heterolytic process that assumes methylenecyclohexadiene 1 as
the intermediate for benzylic compounds (Eq. 1), while the other advocated the electron transfer process
that involves radical cation 2 and benzylic radical 3 as the precursors to side-chain substitution products
(Eq. 2).
We have recently developed a new nitration methodology based on nitrogen dioxide (NO2) and
ozone (kyodai-nitration), which converts a wide variety of aromatic compounds to the corresponding
mononitro to polynitro derivatives under mild conditions and in high yield.3 Nitrogen trioxide (NO3) is
proposed as the initial electrophile, which is highly electron-deficient and oxidizes aromatic substrates
by one-electron transfer process. However, the kyodai-nitration of some polymethylbenzenes is rather
complicated; nitration, nitrooxylation and oxidation of alkyl side-chain take place in parallel with
ordinary ring nitration. This complication may be attributed largely to the versatility of NO3 as the reagent
∗
Corresponding author. Fax: +81 798 51 0914; e-mail: hsuzuki@kwansei.ac.jp (H. Suzuki)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02053-5
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to oxidize an aromatic substrate to a radical cation, to abstract a hydrogen from an alkyl side-chain to
form a benzylic radical, or to add to an aromatic ring to form a cyclohexadienyl radical.
In order to look closer into the nature of these side-chain reactions, we have examined the inter-
and intramolecular deuterium isotope effect of the kyodai-nitration of p-xylene at an early stage of
the reaction. Thus, p-xylene 4 and its partially and fully deuterated derivatives 1,4-(CH3)(CD3)C6H4
4HD and 1,4-(CD3)2C6D6 4DD were nitrated under a variety of conditions and the product distributions
1
were determined by HPLC, GC or H NMR analysis. The reaction was quenched before complete
disappearance of the substrates to avoid further transformation of the initial products. 2,6-Di-tert-butyl-4-
methylpyridine was employed to examine the effect of a base catalyst. The major products were identified
as 4-methylbenzyl nitrate 5, p-tolualdehyde 6, 4-methylphenylnitromethane 7, and 2-nitro-p-xylene 8
(Scheme 1; Table 1). The minor products included 2,5-dinitro-p-xylene, 2-nitro-3,6-dimethylphenol,
2,6-dinitro-p-xylene, and unidentified highly polar substances in the decreasing order. Aldehyde 6 was
probably a secondary product derived from the oxidative degradation of initially formed benzyl nitrite
12.
Scheme 1.
First, the intermolecular isotope effect vH/vD was examined for the consumption of substrates 4 and
4DD using the competition method and the results are summarized in Table 1. The observed value should
reflect the relative contribution of the C–H/C–D bond rupture at substrate-determining stage, the large

231
Table 1
Isotope effect and yield in the nitration of p-xylene 4
values supporting direct abstraction of hydrogen by an attacking species.† In the kyodai-nitration, the
intermolecular isotope effect lies in the range 1.11–1.49, which rules out the possibility of direct hydrogen
abstraction by a NO3 radical as well as direct insertion of a NO2 moiety into the C–H bond of alkyl side-
chain. The back electron transfer may contribute somewhat to the apparent increase of the intermolecular
isotope effect.4
The intramolecular isotope effect values kH/kD of the respective side-chain reactions, i.e. nitrooxylation
5H/5D, oxidation 6H/6D and nitration 7H/7D, were obtained from the kyodai-nitration of partially deute-
rated p-xylene 1HD. A large isotope effect observed in the side-chain nitrooxylation 5H/5D=3.5–5.3 and
oxidation 6H/6D=2.9–4.9 is highly indicative of the bond rupture at site-determining stage. These values
are large enough to overshadow the temperature dependence of the isotope effect in our discussion.5 A
small intermolecular but a large intramolecular isotope effect is consistent with the one-electron transfer
oxidation of substrate 4 by NO3, followed by deprotonation of the resulting radical cation 4·+ to form the
benzyl radical 9, as shown in Scheme 2.
Noteworthy is the small isotope effect 7H/7D observed in the side-chain nitration, which contrasts
with the large 5H/5D values for the side-chain nitrooxylation (entries 1 and 3). This also contrasts to the
+
conventional aromatic nitration based on NO2 ion, where all observed values were small and similar
despite the different product distributions (entries 5–7). These observations are highly suggestive of the
operation of different mechanisms for the formation of side-chain substitution products in the kyodai-
nitration. A plausible explanation for the small 7H/7D value is as follows; the radical cation 4·+ is trapped
†
In the bromination of 4, 4DD and 4HD with NBS-AIBN, the vH/vD and kH/kD values were as high as 6 in accordance with the
direct hydrogen abstraction by bromine atom.

232
Scheme 2.
by NO2 to form arenium ions 10 and 11, the proton release from which would lead to a nitrotriene 13 and
a ring nitration product 8, the ratio of these varying considerably depending on the conditions employed.
The triene intermediate 13 may collapse either heterolytically at the double allylic position to form a pair
of benzyl cation and nitrite anion or homolytically to form an intimate pair of arylmethyl radical and
NO2, eventually leading to arylnitromethane 7 and benzylic nitrate 5.
The arene radical cation 4·+ is highly likely to be a common intermediate for the kyodai-nitration as
well as the non-conventional nitration based on NO2,6 cerium(IV) ammonium nitrate Ce(NH4)2(NO3)6
(CAN),7 and tetranitromethane (TNM).8 However, these reactions usually give rise to considerably
different distributions of side-chain substitution products. However, this is not unexpected. In the kyodai-
nitration at −70°C, where excess NO2 exists mostly in the dimeric form,9 benzyl radical 9 would be
trapped by N2O4 preferentially through the oxygen to give nitrite 12 as the major initial product (entry
1). Added pyridine base would facilitate proton release from the intermediate radical cation 4·+, thus
favoring the formation of the side-chain nitrooxylation and oxidation products 5 and 6 over the ring- and
side-chain nitration products 8 and 7 (entry 2). Under these conditions, nitroxylene 8 accounts for only
a minimal part of the products. A rise in temperature would increase the concentration of NO2, which
works favorably for the formation of ring substitution product 8 at the expense of side-chain substitution
products 5 and 6 (entry 3). In contrast, the reaction of p-xylene and NO2 at room temperature, where
the radical cation 4·+ resulting from the one-electron oxidation6,10 by in situ generated NO+ would lose
proton and couple with NO2 at both nitrogen and oxygen, leading to nitromethane 7 as the major product
together with products 5 and 6 (entry 4). This interpretation is in accord with the observed large values of
5H/5D, 6H/6D and 7H/7D that are in the range 2.5–3.0. In the reaction with CAN (entry 8), the resulting
radical 9 is rapidly oxidized by cerium(IV) to arylmethyl cation, which couples with the nitrate ligand to
form the corresponding nitrate 5 as the main product. The nitration with acetyl nitrate afforded significant
amounts of side-chain substitution products 5 and 7 (entry 6). Low deuterium isotope effect for both
side-chain nitrooxylation and nitration rules out the intervention of radical species 9. Noteworthy is that
the reaction of 4 and N2O5 led to a considerable amount of benzyl nitrate 5 and arylnitromethane 7
(entry 5). The deuterium isotope effect was quite low again, which stands in marked contrast to the

233
observations from the kyodai-nitration. In all these cases, little or no aldehyde 6 was detected. Although
N2O5 can be prepared from NO2 and ozone, an in situ mixture of these two compounds has proved to
behave differently toward aromatic substrates in accordance with the involvement of NO3 as the initial
electrophile in the kyodai-nitration.
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