N-Hydroxyphthalimide (NHPI)/lead tetraacetate reactions with cyclic and acyclic alkenes

Article abstract of DOI:10.1002/poc.1466

The reactions between phthalimide N-oxyl (PINO) radical and cyclohexene, cyclooctene, and trans-3-hexene were carried out. The PINO radical has been in situ generated from its hydroxylimide parent, N-hydroxyphthalimide (NHPI), applying two approaches: usi

Full text of DOI:10.1002/poc.1466

Research Article
Received: 18 August 2008,
Revised: 25 September 2008,
Accepted: 26 September 2008,
Published online in Wiley InterScience: 11 December 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1466
N-Hydroxyphthalimide (NHPI)/lead
tetraacetate reactions with cyclic and
acyclic alkenes
Sergiu Coseria
*
The reactions between phthalimide N-oxyl (PINO) radical and cyclohexene, cyclooctene, and trans-3-hexene were
carried out. The PINO radical has been in situ generated from its hydroxylimide parent, N-hydroxyphthalimide (NHPI),
applying two approaches: using metallic salts, such as lead tetraacetate and cerium (IV) ammonium nitrate (CAN), and
a ‘‘metal free’’ system in which the role of metallic species has been undertaken by antraquinone. In the former case,
the strong influence of lead tetraacetate (or CAN) on the NHPI’s reactivity, induce two different channels for the
reaction pathway, radical and non-radical, a complex mixture of both saturated and unsaturated diadducts together
with the corresponding monoadduct being formed. This behavior will not occur in the case of PINO generation in
non-metallic systems, in this case the reaction pathway proceed exclusively via radical mechanism, with the formation
of monoadducts as sole products. Copyright ß 2008 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: N-hydroxyphthalimide (NHPI); phthalimide N-oxyl (PINO) radical; lead tetraacetate; adducts formation; oxidation
We have carried out further explorations into NHPI’s chemistry,
particularly in the PINO’s reactions with cyclic and acyclic alkenes.
INTRODUCTION
The development of efficient catalytic system for selective
organic transformation is currently one of the challenging tasks in
synthetic organic chemistry.
To check if NHPI/lead tetraacetate presents indeed a particular
behavior in reaction with alkenes, we have used different systems
to generate PINO radical, either metallic [by using cerium (IV)
ammonium nitrate (CAN)] and non-metallic (by using antraqui-
none). On the other hand, lead tetraacetate has been used to
generate besides PINO (1), see Scheme 3, another nitroxyl radical
that is, benzotriazole-N-oxyl (2; BTNO), Scheme 3, from its parent
hydroxylamine (1-hydroxybenzotriazole, HBT) then reacting with
alkenes, 4, 5, and 6, Scheme 3.
In recent years, N-hydroxyphthalimide (NHPI) has been
recognized as a valuable catalyst for the aerobic oxidation of
various organic compounds under mild conditions.[1] It is
generally assumed that these oxidations proceed via intermedi-
ate phthalimide N-oxyl (PINO) radical, able to abstract a hydrogen
atom from the organic substrate.[2] The newly formed carbon
centered radical then readily reacts with dioxygen, to give
ultimately oxygenated compounds, Scheme 1.
The generation of the PINO radicals from its precursor NHPI,
can be achieved by using various methods, including the
well-known ‘‘Ishii catalytic system’’ which implies the use of Co(II)
or Mn(II) salts.[3] However, in the last years, due to metallic toxicity
and high expense, researchers have been concentrated on
developing non-metallic systems, which becomes frequently
used. These metal free systems able to generate NHPI includes
compounds such as: a,a-azoisobutyronitrile,[4] peracids,[5]
dioxirane,[6] NO2,[7] anthraquinones,[8] and others.
Among the metallic salts used for the PINO radical generation,
lead tetraacetate was used for the first time, early on 1964 by
Lemaire and Rassat,[9] using EPR spectroscopy, Scheme 2. PINO
presents a triplet signal with a hyperfine coupling constant in
t-BuOH of aN ¼ 4,36 G, which is smaller than the constants of
other nitroxyl radicals.[10] The g-factor in PINO is larger than that
of other nitroxyl radicals; one explanation could be due to the
presence of acyl groups linked to the nitrogen atom.
Koshino et al.,[2] reported that the molar absorptivity of PINO
generated from NHPI/Pb(OAc)4 in acetic acid, is 1.36 ꢀ
103 L molꢁ1 cmꢁ1 at lmax 382 nm, Fig. 1.
EXPERIMENTAL
General information
High-resolution mass spectroscopy was carried out on a Jeol SX
102 instrument, used for both electron ionization (EI) and fast
atom bombardment (FAB) ionization techniques. Nuclear
magnetic resonance spectra were acquired using a Bruker DPX
400 instrument. The spectra were calibrated where possible to
the signals of tetramethylsilane or the small quantity of CHCl3
present in CDCl3, typically used as the standard solvent for these
*
Correspondence to: S. Coseri, ‘‘Petru Poni’’ Institute of Macromolecular Chem-
istry, 41A, Gr. Ghica Voda Alley, 700487 Iasi, Romania.
E-mail: coseris@icmpp.ro
a
S. Coseri
‘‘Petru Poni’’ Institute of Macromolecular Chemistry, 41A, Gr. Ghica Voda Alley,
700487 Iasi, Romania
J. Phys. Org. Chem. 2009, 22 397–402
Copyright ß 2008 John Wiley & Sons, Ltd.

S. COSERI
Scheme 1.
Scheme 2.
experiments. All 2H NMR spectra were obtained in CHCl3. The T1
allowed to cool to room temperature, the flask was placed in an
ice-bath, and then carefully quenched by dropwise addition
of D2O (7 mL), D2O/DCl (20% DCl, 3 mL) and finally HCl (6 N,
10 mL). The dideuterated compound was extracted into
hexadecane, and the hexadecane layer was washed with water
(5 ꢀ 8 mL), dried with Na2SO4 and filtered. Distillation gave 1.24 g
(14.4 mmol, 50% yield) of the title compound as a clear, colorless
liquid. 1H NMR (CHCl3) d 1.99 (q, 4H, CH2), 1.00 (t, 6H, CH3);
13C NMR (CHCl3) d 130.4 (t), 25.4, 13.9. Deuterium incorporation at
2
relaxation times of the H signals were ꢂ100 ms and the delay
time between pulses was therefore chosen to be 2 s (>> 5 ꢀ T1)
to ensure accurate integration of these signals. Flash column
chromatography on silica was used as a standard purification
procedure using Fluka Kieselgel 60, 0.04–0.063 mm particle size.
Thin layer chromatography was used where possible as a
standard procedure for monitoring the course and rate of a given
reaction. TLC plates used were Merck aluminum backed sheets
with Kieselgel 60 F254 silica coating.
1
the vinylic site was >99% as determined by H NMR.
trans-3,4-Dideuteriohex-3-ene was prepared following
a
modified literature method.[11] In a round-bottom flask fitted
with a reflux condenser slurry of LiAlD4 (1.4 g, 33.6 mmol) in 30 mL
anhydrous diglyme was prepared. To the slurry, 3-hexyne (2.4 g,
28.6 mmol) was added dropwise via syringe. The heterogeneous
mixture was heated to 150 8C for 6.5 h. The mixture was
Alkene reaction with PINO and BTNO radicals
In our first investigation of the mechanism of reaction of PINO
with three alkenes, we oxidized the NHPI with lead tetraacetate or
CAN, at room temperature in deoxygenated acetonitrile, one of
Figure 1. UV/Vis spectrum of PINO (generated from NHPI and lead
tetraacetate) radical in acetic acid
Scheme 3.
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2009, 22 397–402

NHPI/LEAD TETRAACETATE REACTIONS
Scheme 4.
the most suitable solvent for these reagents, which provide both
reasonable solubilities for NHPI and Pb(OAc)4 and easy product
workup. The alkene, NHPI, and Pb(OAc)4 (or CAN) were always
reacted together at molar ratios of 10:2:1. The alkene (0.50 mM)
and NHPI in 5 mL of acetonitrile were added to 5 mL of
acetonitrile solutions of Pb(OAc)4 (or CAN). Shorter after mixing
(less than 15 min), the acetonitrile and excess alkene were
removed under reduced pressure. The mono- and di-PINO alkene
adducts were separated and purified by preparative TLC using
hexane/ethyl acetate (2:1, v/v) as an eluent.
The same procedure was followed in the case of BTNO
(generated from its parent hydroxylamine with lead tetraacetate)
reactions with alkenes, 3, 4, and 5.
The next step to generate PINO radical was to employ a ‘‘metal
free’’ system. We have chosen to use antraquinone, a chemical
system which was shown to form PINO radicals,[8] according with
the Scheme 4.
PINO was generated either in the presence or absence of metallic
species as cocatalyst. Moreover, further information on the
reaction mechanisms involved in these reactions could be
acquire by analyzing the products composition when instead
PINO radical, another nitroxyl radical, BTNO (generate by using
lead tetraacetate) has been employed, and comparing with those
identified in the case of NHPI/lead tetraacetate system.
In one set of experiments, we have synthesized the
trans-3,4-dideuteriohex-3-ene by the lithium aluminum deuter-
ide (LiAlD4) reduction of 3-hexyne, and then react with NHPI/
Pb(OAc)4 system. Deuterium label was chosen because, for both
potentially mechanisms involved, there would be no primary
deuterium kinetic isotope effect, and would considerable simplify
the interpretation of the 2H NMR spectra of the resulted products.
The deuterium labeled alkene, NHPI, and Pb(OAc)4 were used at
molar ratio 10:2:1, at room temperature in deoxygenated
acetonitrile. Products yield based on NHPI were (a) 12%,
(b) 10%, (c) 2.5% (NHPI reacted ¼ 12 þ 2 ꢀ 10 þ 2 ꢀ 2.5 ¼ 37%),
Scheme 6.
In another set of experiments, to ensure that the diadduct c
(Scheme 6) is indeed present in the reaction mixture, a larger
scale reaction was performed, employing unlabeled alkene,
trans-hex-3-ene in reaction with NHPI/Pb(OAc)4 system, in
sufficient quantity to obtain X-ray crystallographic structure of
the unexpected unsaturated diadduct, see Supporting Infor-
mation. The crystallographic structure for the diadduct c has
been deposited to the Cambridge Crystallographic Data Centre,
deposition number CCDC 669756.
The antraquinone/NHPI/alkene experiments were carried out
under oxygen-free conditions, the molar ratio between reagents:
1:4:10. The products were separated in the usual way.
RESULTS AND DISCUSSION
In our previous work,[12] we have used the TEMPO,
di-tert-butyliminoxyl, and PINO radicals, to investigate the
competition between the two possible reaction mechanisms
on the three symmetric alkenes that is, abstraction–addition or
addition–abstraction mechanisms as the first step in these
reactions.
The reaction mechanism was identical for all the studied
reaction systems, except the NHPI/Pb(OAc)4/alkene system, when
it was found that the major product was a diadduct in which two
PINO moieties had added across the double bond of the alkene,
Scheme 5. Interestingly, the diadduct formation was found only in
the case of the reaction when PINO was generated by lead
tetraacetate.
All the unlabeled alkenes were afterwards reacted with the
PINO and BTNO radicals, generated in situ by using different
cocatalysts. The percentages of monosubstituted and disubsti-
tuted adducts are shown in Table 1.
The reactions of both 1 and 2 radicals (when generated in a
‘‘metal free’’ system) with alkenes 3, 4, and 5 are forming
exclusively monoadducts (Table 1, entries 1, 5, 7, 10, 12, and 15).
The diadducts are formed after the reaction of PINO [when
generate by using Pb(OAc)4 or CAN] with the alkenes 3, 4, and 5
(Table 1, entries 3, 4, 8, 9, 13, and 14). BTN radical behave similarly
with PINO, when it is generate within a metallic system
In this paper, we extend the study of PINO radical reactions
with the three alkenes, by comparison the mechanisms when
Scheme 5.
J. Phys. Org. Chem. 2009, 22 397–402
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

S. COSERI
Scheme 6.
Table 1. Percentages of monosubstituted and disubstituted adducts
No.
Radical
Alkene
% Monosubstituted adduct
% Disubstituted adduct
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1 (antraquinone)
*
3
3
3
3
3
3
4
4
4
4
4
5
5
5
5
5
100
100
97
98
100
97
100
60
68
100
76
100
40
0
0
3
2
0
1 (CuCl)
1 (Pb(OAc)4)
1 (CAN)
2 (antraquinone)
2 (Pb(OAc)4)
1 (antraquinone)
1 (Pb(OAc)4)
1 (CAN)
2 (antraquinone)
2 (Pb(OAc)4)
1 (antraquinone)
1 (Pb(OAc)4)
1 (CAN)
3
0
40
32
0
24
0
60
57
0
43
100
88
2 (antraquinone)
2 (Pb(OAc)4)
12
[13]
*
Data from Ref.
(Pb(OAc)4), Table 1, entries 6, 11, and 16. However the yields of
the diadducts formation in this case are slightly lower. The
diadducts formation, which is evident in the NHPI/Pb(OAc)4 or
NHPI/CAN cases, could be explained by considering the
coexistence of both radical and non-radical mechanisms, in
sharp contrast with the NHPI/antraquinone reaction with alkenes,
when only the radical mechanism is operative.
Moreover, in the case of using NHPI/Pb(OAc)4 system, in
reaction with acyclic alkenes, the diadduct formation is a more
complex process. For this reaction system, the saturated diadduct
is not the sole diadduct product, its formation is accompanied,
surprisingly by the presence of unsaturated diadduct, which it is
not found in the cyclic alkenes reaction with NHPI/Pb(OAc)4.
Although, it is generally accepted that PINO radical is the active
species resulted from NHPI activation, in the NHPI/Pb(OAc)4
system, the intervention of some form of Pb(IV) in reaction
introduces two quite different channels for product formation,
Scheme 7.
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J. Phys. Org. Chem. 2009, 22 397–402

NHPI/LEAD TETRAACETATE REACTIONS
Scheme 8.
viz., radical and non-radical reactions. It was expected that PINO
to generate even higher yields of monoadducts than BTNO,
because at least two reasons.
The resulted PINO diadducts could prove their synthetic utility,
being readily converted into corresponding diols or dihydrox-
ylamines species,[19] Scheme 8.
PINO is known to be more stable,[14] an issue which matter if
we take into account the limited stability of the aminoxyl radicals,
and the second is the energy value of the O–H bond that the two
aminoxyl radicals formed after H-abstraction. The BDE (O–H) of
NHPI is larger than that of HBT, that is, 88 kcal molꢁ1 versus
85 kcal molꢁ1, respectively, and therefore the H-abstraction with
NHPI is thermodynamically more favored. The relative equal
percents founded could be explained by the existence of
‘‘non-radical’’ route, dictated in fact by the presence of metallic
species, that is, Pb and Ce, in detriment of ‘‘radical’’ route,
responsible only for the monosubstituted product formation.
Others,[15,16] signaled the ability of PINO radical to adds to the
double bond, and the evidence for the saturated diadduct
formation,[11] but the formation of the unsaturated diadduct
which accompanied the saturated one, as far as we are
concerned, is reported here for the first time. The proposed
reaction mechanism for the trans-hex-3-ene reaction with NHPI/
Pb(OAc)4 which formed mono-, disaturated-, and diunsaturated
diadducts is based on that proposed for the lead tetraacetate
oxidation of cyclohexene to cis- and trans-1,2-diacetoxy-
cyclohexanes and 3-acetoxycyclohexene[17,18] Scheme 7. The
first step of this reaction involves the hex-3-ene/lead triacetate
cation complex formation, then the reaction pathway follow
the both routes, radical and non-radical, giving a mixture of
monoadduct and diadducts, the entropic and enthalpic effects
playing the crucial role for this kind of transformations. In
the alkenes reactions, there is a partial ‘‘freeing’’ or a partial
‘‘freezing’’ of a bond rotation in the transition state, linked with
the enthalpic effects. The alkene/lead triacetate cation complex
formation is supported by the fact that the geometry of the
molecules is the driving force that leads to the 1,2-disubstitued
compounds, in the cyclic alkenes reactions, this adduct represent
in fact the main product. The same route of the reaction is
followed when NHPI/CAN is employed the Ce(IV) substituting the
role of Pb(IV).
CONCLUSIONS
The reactions of alkene/NHPI/antraquinone systems, occurs via
radical mechanism, the sole products being the corresponding
monoadducts.
In sharp contrast, the alkene/NHPI/Pb(OAc)4 and alkene/NHPI/
CAN generates complex mixtures of mono- and diadducts, as an
effect of interpenetration between radical and non-radical
reaction mechanisms, caused by intervention of Pb(IV) and
Ce(IV) species.
Acknowledgements
The author thanks NATO, for the NATO Reintegration Grant,
CBP.EAP.RIG 982044. Thanks are due as well, to Prof. Bogdan C.
Simionescu for his full support and helpful discussions.
REFERENCES
[1] F. Recupero, C. Punta, Chem. Rev. 2007, 107, 3800–3842.
[2] N. Koshino, B. Saha, J. H. Espenson, J. Org. Chem. 2003, 68,
9364–9370.
[3] Y. Ishii, J. Mol. Catal. A: Chem. 1997, 117, 123–137.
[4] Y. Aoki, S. Sakaguchi, Y. Isii, Adv. Synth. Catal. 2004, 346, 199–202.
[5] C. Einhorn, J. Einhorn, C. Marcadal, J.-L. Pierre, Chem. Commun. 1997,
447–448.
[6] F. Minisci, C. Gambarotta, M. Pierini, O. Porta, C. Punta, F. Recupero, M.
Lucarini, V. Mugnaini, Tetrahedron Lett. 2006, 47, 1421–1424.
[7] Y. Nishiwaki, S. Sakaguchi, Y. Ishii, J. Org. Chem. 2002, 67, 5663–5668.
[8] G. Yang, Q. Zhang, H. Miao, X. Tong, J. Xu, Org. Lett. 2005, 7, 263–266.
[9] E. Lemaire, A. Rassat, Tetrahedron Lett. 1964, 5, 2245–2248.
[10] R. Amorati, M. Lucarini, V. Mugnaini, G. F. Pedulli, F. Minisci, F.
Recupero, F. Fontana, P. Astolfi, L. Greci, J. Org. Chem. 2003, 68,
1747–1754.
J. Phys. Org. Chem. 2009, 22 397–402
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

S. COSERI
[11] J. H. Kroll, N. M. Donahue, V. J. Cee, K. L. Demerjian, J. G. Anderson,
J. Am. Chem. Soc. 2002, 124, 8518–8519.
[15] Y. Ishii, T. Iwahama, S. Sakaguchi, K. Nakayama, Y. Nishiyama, J. Org.
Chem. 1996, 61, 4520–4526.
[12] S. Coseri, G. D. Mendenhall, K. Ingold, J. Org. Chem. 2005, 70,
4629–4636.
[16] T. Hara, T. Iwahama, S. Sakaguchi, Y. Ishii, J. Org. Chem. 2001, 66,
6425–6431.
[13] J. M. Lee, E. J. Park, S. H. Cho, S. Chang, J. Am. Chem. Soc. 2008, 130,
7824–7825.
[14] P. Brandi, C. Galli, P. Gentili, J. Org. Chem. 2005, 70, 9521–
9528.
[17] C. B. Anderson, S. Winstein, J. Org. Chem. 1963, 28, 605–606.
[18] K. B. Wiberg, S. D. Nielsen, J. Org. Chem. 1964, 29, 3353–3361.
[19] J. M. Takacs, S. D. Schroeder, J. Han, M. Gifford, X.-T. Jiang, T. Saleh, S.
Vayalakkada, A. H. Yap, Org. Lett. 2003, 5, 3595–3598.
www.interscience.wiley.com/journal/poc
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