Nanometre-sized titanium dioxide-catalyzed reactions of nitric oxide with aliphatic cyclic and aromatic amines

Article abstract of DOI:10.1039/b820535c

Activated on the surface of nanometre-sized TiO₂, NO gas can easily react with aliphatic cyclic amines and aryl free radicals at RT under atmospheric pressure to offer NONOates and cupferron sodiums, respectively. The Royal Society of Chemistry

Full text of DOI:10.1039/b820535c

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Nanometre-sized titanium dioxide-catalyzed reactions of nitric oxide
with aliphatic cyclic and aromatic aminesw
Zhangjian Huang,a Yihua Zhang,*a Lei Fang,a Zhiguo Zhang,a Yisheng Lai,a Ye Ding,a
Fengqi Cao,b Ji Zhangc and Sixun Penga
Received (in Cambridge, UK) 18th November 2008, Accepted 16th January 2009
First published as an Advance Article on the web 18th February 2009
DOI: 10.1039/b820535c
Activated on the surface of nanometre-sized TiO2, NO gas can
easily react with aliphatic cyclic amines and aryl free radicals
at RT under atmospheric pressure to offer NONOates and
cupferron sodiums, respectively.
small inorganic molecules.6b Thus, we envisioned that
nanometre-sized TiO2 may act as a catalyst for the preparation
of NONOates.
To meet the needs of our NO donor drug research, nine
five- or six-membered aliphatic cyclic amines were chosen to
conduct the experiments examining the catalytic potential of
nanometre-sized TiO2 (Table 1).
An increasing knowledge of the role of nitric oxide (NO) in a
number of physiological and pathological processes has sti-
mulated efforts to target the NO pathway pharmacologically.1
Since NO is a pleiotropic molecule, the selective delivery of
NO to the specific tissues has recently been attracting
much attention, particularly in the field of anticancer
therapy.2 Among the various NO donors that directly or
indirectly release NO being used in biomedical research,
nitrogen-bound diazen-1-ium-1,2-diolate (formally known
as NONOate) is the most important, owing to its ability
to deliver NO to some specific tissues.3 Since access to
NONOates generally requires considerably strict conditions,
such as special apparatus, low temperature and/or high
pressure,4 a catalytic method is highly desirable. In continua-
tion of our studies on the site-targeting of NO donor
drugs,5 we developed a novel preparative approach of
NONOates through nanometre-sized TiO2-catalyzed reactions
of NO with aliphatic cyclic amines at RT under atmospheric
pressure, using easily available apparatus. Interestingly, in
expanding this new approach to aromatic amines for the
preparation of their corresponding NONOates, cupferrons,
another kind of useful NO donor, were unexpectedly obtained.
Herein, we report these results and propose the mechanisms
involved.
As can be seen, the reactions in the presence of TiO2
(1.04 mol%) (see the ESI for optimization of the catalyst
loadingw) gave the products in higher yields (89–96%) than
previously reported (33–88%) (Table 1, entries 1, 2, 4, 7 and 8).
Several new compounds were also obtained in nearly
quantitative yields (Table 1, entries 3, 5, 6 and 9). In order
to elucidate the catalytic effect of TiO2, compounds 2c–2f were
prepared in the presence and absence of TiO2 under the
conditions shown in Table 1, with a reaction time of 5 h. It
was found that the product yields in the former case were 52,
50, 72 and 79%, respectively, three- to six-fold higher than
those in the latter case (18, 12, 19 and 13%, respectively),
indicating that the nanometre-sized TiO2 does promote the
reactions.
All structures of the NONOates obtained by this novel
approach were established by 1H NMR and elemental analysis.
In addition, the geometry of the NQN double bond of the
Table 1 Nanometre-sized TiO2-catalyzed reactions of NO with
aliphatic cyclic aminesa
The adsorption of NO onto a single crystal TiO2(110)
surface has been widely utilized in various fields, including
pollution control, NO gas sensors and so on.6a Some theoretical
and experimental studies have already demonstrated
the adsorptive and photocatalytic functions of TiO2 for
Yield
(lit. yield) (%)c
Entry
Aliphatic cyclic amine
1
2
3
4
5
6
7
8
9
Pyrrolidine (1a)
Piperidine (1b)
90 (54)7a
89 (70)7b
89
4-Hydroxypiperidine (1c)b
N-hydroxyethyl piperazine (1d)
N-methyl piperazine (1e)b
N-isopropyl piperazine (1f)b
N-Boc piperazine (1g)
N-phenyl piperazine (1h)
N-benzyl piperazine (1i)b
a Center of Drug Discovery, China Pharmaceutical University,
Nanjing 210009, PR China. E-mail: zyhtgd@sohu.com;
Fax: +86 25 86635503; Tel: +86 25 83271186
96 (88)7c
96
90
b Department of Inorganic Chemistry, China Pharmaceutical
University, Nanjing 210009, PR China
92 (42)7d
94 (33)7d
85
c Department of Physical Chemistry, China Pharmaceutical
University, Nanjing 210009, PR China
a
w Electronic supplementary information (ESI) available: Typical
experiment procedures and analytical data for the products, as well
as crystallographic data for 3i, 6a and 3h. CCDC 705768–705770. For
ESI and crystallographic data in CIF or other electronic format, see
DOI: 10.1039/b820535c
All reactions were run with 1.04 mol% TiO2; the reaction times were
the same as those for the previously reported compounds (24–48 h),
b
and 48 h for the unreported compounds. Unreported compounds.
c
Yield of the isolated product.
ꢀc
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NONOates (Table 1) was determined by single-crystal X-ray
diffraction analysis using two representative compounds: 3h
(CCDC 705770w), an O2-methylated derivative of 2h, and 3i
(CCDC 705768w), a hydrochloride salt of the O2-methylated
derivative of unreported compound 2i (recrystallization of
NONOates 2 is impossible due to decomposition).8 In order
to elucidate other important characteristics of the NONOates
for further medicinal research, NO release and their half-lives
in vitro were also assayed (see the ESIw).
Table 2 Nanometre-sized TiO2-catalyzed reactions of NO with
aromatic primary aminesa
Yield
Recovery
Entry
Arylamine
R
of 5 (%)b
of 4 (%)c
Recently, DeRosa et al. reported9 that high pressure
methods for the preparation of NONOates have the dis-
advantage that NO could react with MeONa in MeOH to
form the side product sodium formate. In contrast, under our
reaction conditions (Table 1), the side reaction was greatly
suppressed and the yield of the side product (only a trace
amount) was much lower than previously reported (7.7%).
Thanks to this result, MeONa could still be employed as the
base when MeOH was used as the solvent in our reactions,
instead of the expensive and not easily available sodium
trimethylsilanoate.9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4-OMe
4-SMe
4-Me
3-Me
2-Me
3,5-di-Me
2,3-di-Me
4-Et
4-i-Pr
H
4-Cl
77
60
66
74
—
61
—
69
57
—
—
—
—
—
48
60
56
61
89
72
90
71
79
89
90
91
90
88
4-CN
4-NO2
3-NO2
Next, we tried to propose a plausible mechanism for the
TiO2-catalyzed preparation of NONOates. It is known that
NO, as a radical molecule, has one electron in its 2p orbital.
This electron can easily transfer to a metal atom’s d orbital
when NO is adsorbed onto its surface, leading to the forma-
tion of a nitrosonium ion NO+.6c When NO is adsorbed onto
the surface of TiO2(110), the preferred configuration might be
either a Ti–NO or Ti–cis-N2O2 orientation6a (Scheme 1).
Through an analysis of the distribution of electron density in
the molecule–slab system, it was found that upon adsorption,
there is a clear polarization of NO or N2O2, with an increase of
the electronic charge in the region between the N and Ti
atoms.6a It is likely that the adsorption of NO onto the surface
of TiO2(110) could decrease the electron density around the N
atom, inducing a certain positive electrical character (d+) on
the NO or N2O2. The mechanism proposed by Drago et al. for
the formation of NONOates in high pressure reactions of
diethylamine with NO demonstrated that the attack of the
lone pair electrons of the nitrogen of secondary amines on the
NO is the rate determining step.10 So, the induced d+ of NO in
our case might accelerate this key step and our proposed
mechanism is illustrated in Scheme 1(a). However, an alter-
native mechanism, the attack of secondary amines on N2O2 to
generate the NONOates (Scheme 1(b)), could not be excluded,
despite the fact that the attack of base on N2O2 in the
a
All reactions were run with 1.04 mol% TiO2 (according to the
b
optimized catalyst loading for the NONOates’ preparation). Yield
c
of the isolated product based on the reacted arylamines. Yield of the
isolated product (see the ESIw).
absence of TiO2 was denied according to the observed kinetic
data.10
It is obvious that nanometre-sized TiO2 does catalyze the
reactions of NO with five- or six-membered cyclic amines.
Compared to the reported methods,4 this novel approach has
several advantages, such as higher yields, more convenient
operation at RT under atmospheric pressure and a more
economical application for the large scale preparation of
NONOates.
Next, we extended this approach to aromatic amines for the
preparation of their corresponding NONOates. Surprisingly,
cupferron sodium salts were obtained from arylamines bearing
electron donating para- and/or meta-substituent(s) on the
benzene ring (Table 2, entries 1–4, 6, 8 and 9), instead of the
desired NONOates.
The structures of the cupferron sodium salts were
established by 1H NMR and elemental analysis (see the ESIw).
The geometry of NQN double bond in 5 was identified by
single crystal X-ray diffraction analysis (see representative
compound 6a (CCDC 705769w), an O2-methylated derivative
of 5a).
Actually, many attempts have been made to synthesize
NONOates through the reaction of NO with primary aryl-
amines, but differing results have been obtained. Drago and
Karstetter reacted NO with aniline at RT under high pressure,
or at À78 1C under atmospheric pressure, but didn’t obtain
any of the desired NONOate,7b whereas Keefer’s group
obtained NONOate ammonium salts from the reactions of
NO with substituted anilines after 24 h at À78 1C under high
pressure.11 Interestingly, in our case, cupferron sodium salts
were formed in the presence of MeONa and nanometre-sized
TiO2 after 48 h at RT under atmospheric pressure.
Scheme 1 The proposed mechanisms underlying the nanometre-sized
TiO2-catalyzed reaction of NO with aliphatic cyclic amines.
ꢀc
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One question that has arisen is why cupferrons were
obtained instead of NONOates. Ohsawa and co-workers
reported that the reactions of NO with aromatic primary
amines at RT under atmospheric pressure in THF resulted
in the corresponding deaminated product via an aryl radical
mechanism.12 The differences in our reaction conditions lay in
using MeONa as a base and nanometre-sized TiO2 as a
catalyst. As a matter of fact, when 4a was used as the substrate
to conduct the reaction under the same conditions as those in
Table 1, using benzene as the solvent, 4-methoxybiphenyl was
obtained as a side product in a 6.3% yield, indicating that it
was formed via an intermediate 4-methoxyphenyl radical,
probably derived from phenyl diazonium salts.12 Therefore,
it is likely that the attack of an aryl radical on the NO led to
the cupferrons. Noticeably, without TiO2, cupferron 5a could
not be isolated from the reaction. Thus, we suggest that an
aryl radical electron donor could react with NO to form a
cupferron, probably under the following conditions and processes.
Firstly, nanometre-sized TiO2 induces a d+ charge on the N
atom of NO or N2O2; secondly, para- or meta-substituted
electron donating groups have a certain ability to enhance the
electron density of the aryl radical; thirdly, no electron with-
drawing groups and/or sterically hindered ortho-substituents
exist; last but not least, the aryl radical could initially react
with NO to form an intermediate, which might subsequently
react with another NO molecule and gain an electron from the
arylamine-containing reaction medium, finally generating the
cupferron. This probably induces the generation of aryl free
radicals starting from arylamine in the reaction mixture to
react with NO again. The proposed mechanism is depicted in
Scheme 2.
improve the yields of cupferrons and investigate their
pharmacological applications.
In conclusion, we have developed a novel nanometre-sized
TiO2-catalyzed preparation of NONOates and cupferrons
through the reactions of NO gas with the corresponding
amines at RT under atmospheric pressure. The corresponding
mechanisms have also been proposed. Importantly, our
investigations might not only expand the fields of NO gas
involving reactions such as the free radical reactions of NO
with alkene or alkyne, but also promote the studies on
targeting of NO donor drugs. Further investigations into the
applications of this novel method are under way and the
results will be reported in due course.
The authors thank the Research Fund for the Doctoral
Program of Higher Education of China no. 20070316007 for
financial support
Notes and references
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To the best of our knowledge, we are the first to report the
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Scheme 2 The proposed mechanisms for nanometre-sized TiO2-
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catalyzed reactions of NO with aromatic primary amines.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1763–1765 | 1765