Influence of substitution at the benzylic position on the behavior of stereoisomeric phosphorus compounds as precursors of stabilized carbon-centered radicals

Article abstract of DOI:10.1021/ol051254y

(Chemical Equation Presented) Efficient benzylic radical formation from benzo[d]-1,2-oxaphospholes has demonstrated their suitability as precursors of stabilized C-centered radicals, a property associated with antioxidant potential. A remarkable stereodifferentiation is observed for alkyl- and aryl-substituted derivatives.

Full text of DOI:10.1021/ol051254y

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3869-3872
Influence of Substitution at the Benzylic
Position on the Behavior of
Stereoisomeric Phosphorus Compounds
as Precursors of Stabilized
Carbon-Centered Radicals
Julia Pe´rez-Prieto,*,† Raquel Eugenia Galian,† Pascual On˜a Burgos,‡
Maria del Carmen Morant Min˜ana,† Miguel Angel Miranda,§ and
Fernando Lo´pez-Ortiz*,‡
Departamento de Qu´ımica Orga´nica/ICMOL, UniVersidad de Valencia, AV. Vicent
Andre´s Estelle´s s/n, 46100 Burjassot, Valencia, Spain, AÄ rea de Qu´ımica Orga´nica,
UniVersidad de Almer´ıa, Carretera de Sacramento s/n, 04120 Almer´ıa, Spain, and
Departamento de Qu´ımica/Instituto de Tecnolog´ıa Qu´ımica UPV-CSIC, UniVersidad
Polite´cnica de Valencia, Camino de Vera s/n, 46071 Valencia, Spain
julia.perez@uV.es
Received May 27, 2005
ABSTRACT
Efficient benzylic radical formation from benzo[d]-1,2-oxaphospholes has demonstrated their suitability as precursors of stabilized C-centered
radicals, a property associated with antioxidant potential. A remarkable stereodifferentiation is observed for alkyl- and aryl-substituted derivatives.
Antioxidants capable of blocking free-radical chain processes
must meet two requirements: (1) they should be good
hydrogen donors and (2) the resulting radicals should exhibit
low reactivity toward oxygen.1
in Scheme 1). If the new radicals have suitable absorption
bands, their formation and reactivity can be studied by the
laser flash photolysis (LFP) technique.
One of the strategies to determine the ability of a molecule
to act as antioxidant is the use of transient absorption
spectroscopy to investigate the reactivity of tert-butoxy
radicals toward H-donors (Scheme 1). Thus, upon laser
excitation of di-tert-butyl peroxide, the O-O bond dissoci-
ates, affording two tert-butoxy radicals. These species decay
by reaction with the solvent (acetonitrile in Scheme 1),
â-cleavage, and reaction with peroxide.2 The above processes
can compete with hydrogen abstraction when the irradiation
is performed in the presence of a good hydrogen donor (R-H
Scheme 1. Generation of tert-Butoxyl Radicals and
Subsequent Reactions
† Universidad de Valencia.
‡ Universidad de Almer´ıa.
§ Universidad Polite´cnica de Valencia.
(1) Burton, G. W.; Doba, T.; Gabe, E. J.; Hughes, L.; Lee, F. L.; Ingold,
K. U. J. Am. Chem. Soc. 1985, 107, 7053. Das, P. K.; Encinas, M. V.;
Steenken, S.; Scaiano, J. C. J. Am. Chem. Soc. 1981, 103, 4162. Ingold, K.
U. Acc. Chem. Res. 1969, 2, 1.
10.1021/ol051254y CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/05/2005

Figure 1. Compounds leading to stabilized C-centered radicals.
In particular, hydrogen abstraction from benzylic positions
by tert-butoxy radicals occurs with convenient rate constants
(toluene: k2 ) 0.23 × 106 M-1 s-1, 2-phenylethane: k2 )
1.05 × 106 M-1 s-1, diphenylmethane: k2 ) 0.91 × 106 M-1
s-1);2,3 the resulting C-centered radicals show an intense
absorption band at λmax >310 nm.4 Electron-withdrawing
substituents at the benzylic position, as in aryl acetates,
usually slow the hydrogen abstraction rate due to the
electrophilicity of the tert-butoxy radical;5 this does not
happen with arylacetonitriles (1 and 2) or lactones 3 (Figure
1).6,7 In addition, though benzylic radicals usually show high
reactivity toward oxygen,8 limiting the potential use of their
precursors as antioxidants, those derived from compounds
1-3 remain practically unreactive in the time-scale of LFP
measurements.6,7 The unique behavior of these systems has
been attributed to the combined effect of some of the
following parameters: (1) benzylic resonance stabilization,
(2) spin delocalization into the carbonyl or cyano heteroatom,
(3) electron-withdrawing effects, (4) steric effects, and in
the case of compounds 3, also (5) the forced planarity
introduced by the five-membered rings.
We have previously reported that benzo[d]oxaphospholes
4-6 can be useful as precursors of stabilized carbon-centered
radicals (Figure 2).9 Interestingly, the presence of phosphorus
in their structure gives rise to the formation of two diaste-
reoisomers. In the case of 5 and 6, this structural feature
has allowed the study of diastereodifferentiation in hydrogen
abstraction by tert-butoxy radicals. It has been found that
the compounds with the aryl substituents trans to the ethoxy
group are much more reactive than their cis stereoisomers.
Figure 2. Phosphorus compounds.
We wish now to report on the results obtained with
3-alkyl-substituted derivatives 9-11, whose study was
undertaken in order to understand the factors involved in
the intriguing diastereodifferentiation observed with 5 and
6. In addition, compounds 7 and 8, lacking the substituent
at the benzylic position, as well as the noncyclic analogues
12, have been also studied to determine whether the
phosphorus-containing heterocycle plays a key role. Fur-
thermore, steady-state photolysis studies have been carried
out; the main products are diasteroisomers resulting from
cross-coupling between the oxaphosphole system and the
solvent. These products are formed in a diastereomeric ratio
that is independent from the precursor configuration, indicat-
ing that the C-centered radical does not show any memory
effect.
The required oxaphospholes were synthesized in a two-
step sequence involving addition of an organometallic reagent
or reduction with NaBH4 of the corresponding commercially
available 2-hydroxyaldehyde and subsequent treatment of the
resulting hydroxyalkylphenols with triethyl phosphite (for
details see the Supporting Information). The structure of the
new products was assigned on the basis of the large coupling
(2) Tsentalovich, Y. P.; Kulik, L. V.; Gritsan, N. P.; Yurkovskaya, A.
V. J. Phys. Chem. A 1998, 102, 7975. Small, R. D., Jr.; Scaiano, J. C. J.
Am. Chem. Soc. 1978, 100, 4520. R. D. Small, R. D., Jr.; Scaiano, J. C. J.
Am. Chem. Soc. 1978, 100, 296.
(3) Arends, I. W. C. E.; Mulder, P.; Clark, K. B.; Wayner, D. D. M. J.
Phys. Chem. 1995, 99, 8182.
(4) McClelland, R. A.; Cozens, F. L.; Steenken, S.; Amyes, T. L.;
Richard, J. P. J. Chem. Soc., Perkin Trans. 2 1993, 1717. McClelland, R.
A.; Kanagasabapathy, V. M.; Steenken, S. J. Am. Chem. Soc. 1988, 110,
6913. Mittal, J. P.; Hayon, E. Phys. Sci. 1972, 240, 20.
(5) Paul, V.; Roberts, B. P.; Willis, C. R. J. Chem. Soc., Perkin Trans.
2 1989, 1953.
(6) Bejan, E. V.; Font-Sanchis, E.; Scaiano, J. C. Org. Lett. 2001, 3,
4059. Scaiano, J. C.; Martin, A.; Yap, G. P. A.; Ingold, K. U. Org. Lett.
2000, 2, 899.
constant between the phosphorus nucleus and the methine
carbon of the five-membered ring (average value of JPC
1
>
119 Hz). The relative configuration was determined by means
of 1D gNOESY experiments. Selective inversion of the
methylene protons of the ethoxy group produced a NOE
enhancement on the nearby protons of the benzylic substitu-
ent for compounds having a cis arrangement of these moieties
(Figure S4, Supporting Information).
LFP (Nd:YAG laser, λexc ) 355 nm, 10 ns pulse) of
deaerated mixtures of di-tert-butyl peroxide and acetonitrile
(50% v/v) containing the phosphorus compounds 12a-g did
(7) Font-Sanchis, E.; Aliaga, C.; Focsaneanu, K. S.; Scaiano, J. C. Chem.
Commun. 2002, 1576.
(8) Most C-centered radicals are highly reactive towards oxygen:
Maillard, N.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. 1983, 105, 5095.
(9) Pe´rez-Prieto, J.; Galian, R. E.; Miranda, M. A.; Catalina, F.; Mart´ın-
Vargas, N.; Lo´pez-Ortiz, F. Org. Lett. 2004, 6, 561. Pe´rez-Prieto, J.; Galian,
R. E.; Miranda, M. A.; Catalina, F.; Mart´ın-Vargas, N.; Lo´pez-Ortiz, F.
Org. Lett. 2004, 6, 2639.
3870
Org. Lett., Vol. 7, No. 18, 2005

Table 1. Comparison between the Relative Efficiencies (vs
HP-136) of Phosphorus Heterocycles 4-11 as Hydrogen
Donors, Together with the Diastereodifferentiation Factors
(Where Applicable)
relative
efficiency
(vs HP-136) compd (vs HP-136)a
relative
efficiency
diastereo-
differentiation
factor
compd
4
2.19
(RP,R)-5
(RP,R)-6
7
(RP,R)-9
(RP,R)-10
(RP,R)-11
0.19
0.42
0.23
0.47
0.27
0.38
(RP,S)-5
(RP,S)-6
1.38
1.48
0.14
0.28
(RP,S)-9
(RP,S)-10
(RP,S)-11
0.31
0.09
0.04
1.52
3.00
9.50
a HP-136: 5,7-di-tert-butyl-3-(3,4-dimethylphenyl)benzo[b]furan-2-one.
However, this was only true for the trans stereoisomers.
Besides, a remarkable influence of substitution at the benzylic
position on the behavior of the stereoisomeric phosphorus
compounds was observed: while in aryl-substituted deriva-
tives the trans-stereoisomer showed higher efficiency of
radical formation, the cis-isomer was more reactive in the
alkyl-substituted analogues.
Figure 3. (A) Transient absorption spectrum recorded following
laser excitation (355 nm) of a sample containing (Rp,R-11) (10
mM) in di-tert-butyl peroxide/acetonitrile (50/50 v/v), under
nitrogen, 2 µs after the laser pulse. (B) Transient kinetic traces
recorded at 400 nm following 355 nm laser excitation of a sample
containing 10 mM of either (Rp,R)-11 [under nitrogen (O) and
oxygen (9)] or (Rp,S)-11 [under nitrogen (b)] in di-tert-butyl
peroxide/acetonitrile (50/50 v/v).
Diastereodifferentiation could be explained by the steric
hindrance associated with a tert-butoxy radical approach to
the hydrogen atom and by the degree of planarity of the
benzo[d]oxaphosphole system. The first factor would pre-
dominate in the alkyl derivatives. Such steric effects would
be also present in the aryl-substituted compounds. However,
in these cases, the stabilization of the transition state leading
to the benzylic radical would be less favorable for the
stereoisomer with a cis arrangement of the ethoxy and aryl
substituents. The degree of planarity required for an efficient
electronic delocalization of the developing radical center
through the aryl substituent would cause larger steric
interactions in the cis stereoisomer as compared with the
situation in the trans derivatives (see the modelization of
methyl- and phenyl-substituted benzooxaphosphole diaster-
eomeric pairs in Figure S18, Supporting Information).
Finally, product studies with (RP,R)-5 and (RP,S)-5 were
performed in order to determine the type of products formed
in the absence of air. Interestingly, three cross-coupling
products arising from reaction between C-centered radicals
(a solvent-derived radical and the benzylic radical) were
observed, namely the pair of diastereoisomers 13 and the
product of partial hydrolysis of the phosphonate moiety (14).
The same diastereomeric ratio (5:1 as measured by GC/MS)
of compounds 13 was obtained independently of the con-
figuration of the oxaphosphole. However, as expected from
the relative efficiencies of hydrogen abstraction (Table 1), a
higher yield of product formation was obtained in the case
of the (RP,S)-5 stereoisomer. It is very interesting that no
homodimers are formed. A reasonable explanation could be
based on the Fischer-Ingold persistent free-radical effect,
which in the case of persistent and transient radicals always
favors the formation of the cross dimer.11
not produce any detectable transient absorption spectra in
the UV-vis range. Compound 12h led to the typical
spectrum of phenoxy radicals (not shown),10 so no hydrogen
abstraction from the benzylic C-H bond was detected. These
results clearly demonstrate low reactivity of the noncyclic
phosphoric compounds 12, which must be related with the
low nucleophilicity of the benzylic C-H bond. Thus, it
seems that planarity is essential for an adequate reactivity.
Benzo[d]-1,2-oxaphospholes 7-11 were studied under
similar conditions, and the results were compared with those
obtained with 4-6. The transient absorption spectrum,
together with the transient kinetic traces, is shown in Figure
3 for 11; similar results were obtained for 7-10. In all cases,
the rates of growth and decay of the benzylic radicals were
essentially the same in the presence of oxygen as under
nitrogen, indicating a low reactivity toward oxygen in the
LFP time scale (kO2 < 5 × 103 M-1 s-1) [Figure 3B, kinetic
traces under nitrogen and air for (RP,R)-11].
As expected from radical stability considerations, alkyl
substituents were less efficient than aryl groups in promoting
H-atom abstraction from the benzo[d]-1,2-oxaphospholes.
(10) MacFaul, P. A.; Ingold, K. U.; Lusztyk, J. J. Org. Chem. 1996, 61,
1316. Kandori, H.; Kemnitz, K.; Yoshihara, K. J. Phys. Chem. 1992, 96,
8042.
Org. Lett., Vol. 7, No. 18, 2005
3871

has demonstrated the suitability of the former as precursors
of stabilized C-centered radicals, a property associated with
antioxidant potential. Using both diastereoisomers of 3-sub-
stituted benzo[d]-1,2-oxaphospholes, a remarkable stereo-
differentiation is observed for alkyl and aryl-substituted
derivatives. Finally, two cross-coupling compounds, arising
from coupling between substrate- and solvent-derived radi-
cals, are obtained. The lack of diastereodifferentiation in their
formation reveals that, once formed, the benzylic radicals
do not show any memory effect.
With the acyclic material 12c, the product arising from
reaction between the solvent-derived radical and the benzylic
radical was also observed. However, as expected from the
low efficiencies of hydrogen abstraction from this substrate,
a much lower yield of product formation was obtained than
when using (RP,S)-5 under the same conditions (9% for the
former as compared with 85% for the latter, after 20 h of
irradiation, see Figures S16 and S17 in the Supporting
Information).
Acknowledgment. This work was supported by the
Spanish Government (Project Nos. BQU2002-0377 and
PPQ2001-3266). R.E.G and M.C.M.M gratefully acknowl-
edge the Fundacio´n Jose´ y Ana Royo for the posdoctoral
and doctoral fellowships, respectively.
In summary, the behavior of phosphorus compounds with
a hydrogen atom at the benzylic position toward tert-butoxy
radicals has revealed the importance of planarity for H-
abstraction to compete with the natural decay of tert-butoxy
radicals. Comparison of the efficiency in benzylic radical
formation between benzo[d]-1,2-oxaphospholes and HP-136
Supporting Information Available: Transient kinetic
traces for 7, 9, and 10, as well as experimental procedures
and spectroscopic data for all new compounds. Also, a
modelization of methyl- and phenyl-substituted benzooxa-
phosphole diastereomeric pairs is included. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Fischer, H. J. Am. Chem. Soc. 1986, 108, 3925.
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