Benzo[d]-1,2-oxaphospholes as Precursors of Stabilized C-Centered Radicals

Article abstract of DOI:10.1021/ol036345e

(Matrix presented) Several benzo[d]-1,2-oxaphosphole 2-oxides were examined as potential precursors of stabilized C-centered radicals. The transient absorption spectra obtained after laser flash photolysis in the presence of di-terf-butyl peroxide showed

Full text of DOI:10.1021/ol036345e

ORGANIC
LETTERS
2
004
Vol. 6, No. 4
61-564
Benzo[d]-1,2-oxaphospholes as
Precursors of Stabilized C-Centered
Radicals
5
Julia P e´ rez-Prieto,* Raquel E. Galian, Miguel Angel Miranda,‡
,
†
†,‡
§
|
,|
Fernando Catalina, Nuria Mart ´ı n-Vargas, and Fernando L o´ pez-Ortiz*
Departamento de Qu ´ı mica Org a´ nica/ICMOL, UniVersidad de Valencia,
AV. Vicent Andr e´ s Estell e´ s s/n, 46100 Burjassot, Valencia, Spain, Departamento de
Qu ´ı mica/Instituto de Tecnolog ´ı a Qu ´ı mica UPV-CSIC, UniVersidad Polit e´ cnica de
Valencia, Camino de Vera s/n, 46022 Valencia, Spain, Instituto de Ciencia y
Tecnolog ´ı a de Pol ´ı meros, CSIC, Departamento de Fotoqu ´ı mica, C/ Juan de la CierVa
3, 28006 Madrid, Spain, and UniVersidad de Almer ´ı a, AÄ rea de Qu ´ı mica Org a´ nica,
Carretera de Sacramento s/n, 04120 Almer ´ı a, Spain
julia.perez@uV.es
Received December 2, 2003
ABSTRACT
Several benzo[d]-1,2-oxaphosphole 2-oxides were examined as potential precursors of stabilized C-centered radicals. The transient absorption
spectra obtained after laser flash photolysis in the presence of di-tert-butyl peroxide showed the features of benzylic radicals with formation
and decay kinetics not significantly influenced by the presence of oxygen. In the case of compounds with two possible diastereomeric forms,
the C−H bond of the cis-isomers is more reactive toward hydrogen abstraction.
Antioxidants are compounds which protect organic materials
polymers, oils) and living organisms against oxidative
degradation. In the case of chain-breaking antioxidants, their
mechanism of action is based on interference with one of
the propagation steps. In this case, they must meet two
requirements: (1) they should be good hydrogen donors, and
carbon-centered radicals are too reactive toward oxygen.2,3
This is not usually the case for good hydrogen donors
possessing reactive C-H bonds. Interestingly, carbon-
centered radicals derived from lactones such as 2-coumara-
(
1
4
none react only sluggishly with oxygen. In particular, 5,7-
di-tert-butyl-3-(3,4-di-methylphenyl)benzo[b]furan-23-one (HP-
5
(2) the resulting radicals should exhibit low reactivity toward
136, for structure see Figure 1B) has been patented and
oxygen. By contrast with heteroatom-centered radicals, most
(
2) (a) Maillard, B.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
†
Universidad de Valencia.
Universidad Polit e´ cnica de Valencia.
Instituto de Ciencia y Tecnolog ´ı a de Pol ´ı meros.
Universidad de Almer ´ı a.
1983, 105, 5095. (b) Scaiano, J. C.; Tanner, M.; Weir, D. J. Am. Chem.
Soc. 1985, 107, 4396.
(3) (a) Das, P. K.; Encinas, M. V.; Steenken, S.; Scaiano, J. C. J. Am.
Chem. Soc. 1981, 103, 4162. (b) Burton, G. W.; Ingold, K. U. Acc. Chem.
Res. 1986, 19, 194.
(4) Scaiano, J. C.; Martin, A.; Yap, G. P. A.; Ingold, K. U. Org. Lett.
2000, 2, 899. Bejan, E.; Font-Sanch ´ı s, E.; Scaiano, J. C. Org. Lett. 2001,
3, 4059.
(5) (a) Nesvadba, P.; Evans, S.; Kr o¨ hnke, Ch.; Zingg, J. Ger. Offen.
4432732, 1994; Chem. Abstr. 1995, 123, 55685. (b) Nesvadba, P.; Bugnon,
L.; Dubs, P.; Evans, S. Synlett 1999, 863.
‡
§
|
(1) (a) Al-Malaika, S. Int. Mater. ReV. 2003, 48, 165. (b) Migdal, C. A.
Chem. Ind. 2003, 90, 1. (c) Heim, K. E.; Tagliaferro, A. R.; Bobilya, D. J.
J. Nutr. Biochem. 2002, 13, 572. (d) Abbott, T. P.; Wohlman, A.; Isbell, T.
Momany, F. A.; Cantrell, C.; Garlotta, D. V.; Weisleder, D. Ind. Crops
Prod. 2002, 16, 43. (e) Burton, G. W.; Ingold, K. U Acc. Chem. Res. 1986,
1
9, 194. (f) Mahoney L. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 547. (g)
Ingold, K. U. Chem ReV. 1961, 61, 563.
1
0.1021/ol036345e CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004

nonbonding oxygen p-type orbitals, oriented more or less in
the OdX-O (X ) P or C) plane. The X atom provides only
8b,9
negligible contribution to the SOMO. For instance, in the
case of benzoyloxy radicals theoretical calculations predict
spin densities of 0.54 on each oxygen and -0.10 on the
9
a
carbonyl carbon.
With this as background, it appeared of interest to study
the suitability of benzo[d]-1,2-oxaphosphole 2-oxides (3)
(
which could be considered as the phosphorus analogues of
HP-136) as good hydrogen donors, leading to C-centered
stabilized radicals. It has been reported that C -unsubstituted
derivatives of 3 behave as heat stabilizers and antioxidants
R
1
0
for organic materials.
Several routes are available for the preparation of benzo-
[
d]-1,2-oxaphosphole 2-oxides bearing an ample pattern of
11
substituents on the carbon adjacent to phosphorus. How-
ever, the phosphorus analogues of lactone HP-136 have not
been previously described. The target compounds were
synthesized in a two steps sequence involving the addition
of an aryl organometallic reagent to the commercially avail-
able aldehyde 1 and subsequent treatment of the resulting
hydroxyalkylphenols 2 with PBr
3 1
/HBr and then with R P-
(
OEt) (R ) OEt, Ph). Oxaphospholes 3 were obtained as
2
1
mixtures of diastereomers (Scheme 1, Table 1). The pure
Figure 1. Transient absorption spectra following laser excitation
355 nm) of a sample containing 3a (2.5 mM) or HP-136 (7.5 mM)
in di-tert-butyl peroxide/acetonitrile (50/50), under nitrogen, 6 µs
after the laser pulse.
(
Scheme 1a
commercialized by CIBA as an antioxidant preventing
oxidative degradation of a variety of materials. Also, it has
been reported that substitution of carbon-centered radicals
6
by the cyano group has a marked stabilizing effect. In
general, the stability of all the above radicals has been
explained on the basis of spin density on heteroatom- and/
or electron-withdrawing effects adding to stabilization by
benzylic delocalization.
On the other hand, the formation of C-centered radicals
attached to a phosphorus atom has been previously de-
7
scribed. The evidence is strongly against any significant
C-P dπ-pπ bonding in the ground state of these radicals
and agrees with spin-density essentially localized on the
carbon atom. Furthermore, phosphonoyloxyl radicals are
similar to carbonyloxyl radicals and have broad and unstruc-
a
+
Key: (1) ArLi (2.2 equiv), Et
then chromatography; (3) R P(OEt)
for R (0.4 equiv), 47% HBr (1 drop), toluene, -30
2
O, -40 to +25 °C, 2 h; (2) H
3
O ,
1
2
(2 equiv for R ) Ph; 3 equiv
1
1
) OEt), PBr
3
8
tured absorption spectra in the visible region. ESR experi-
to +25 °C, 6-12 h; (4) 1N NaOH.
ments and theoretical studies have shown that the unpaired
electron resides mainly in an orbital composed largely of
compounds were isolated through a combination of precipi-
tation from hexane and column chromatography. In one case,
partial hydrolysis of the phosphonate group leading to 3a
was achieved simply by quenching the reaction with ice-
water. Under these conditions, the heterocyclic system was
(
6) (a) Huang, R. L. J. Chem. Soc. 1956, 1749. (b) Bellus, D.; Rist, G.
HelV. Chim. Acta 1974, 57. 194. (c) Clarke, L. F.; Hegarty, A. F.; O’Neill,
P. J. Org. Chem. 1992, 57, 362. (d) Font-Sanch ´ı s, E.; Aliaga, C.;
Focsaneanu, K. S.; Scaiano, J. C. Chem. Commun. 2002, 1576. (e) Font-
Sanch ´ı s, E.; Aliaga, C.; Bejan, E. V.; Cornejo, R.; Scaiano, J. C. J. Org.
Chem. 2003, 68, 3199.
(
7) (a) Begum, A.; Lyons, A. R.; Symons, M. C. R. J. Chem. Soc. A
1
2
3
971, 2388. (b) Geoffroy, M.; Ginet, L.; Lucken, E. A. C. Mol. Phys. 1974,
8, 1289. (c) Geoffroy, M.; Ginet, L.; Lucken, E. A. C. Mol. Phys. 1977,
4, 1175. (d) Bhat, S. N.; Berclaz, T.; Jouaiti, A.; Geoffroy, M. HelV. Chim.
Acta 1994, 77, 372. (e) Aguila, A.; O’shea, K. E.; Tobien, T.; Asmus, K.-
D. J. Phys. Chem. A 2001, 105, 7834.
(9) (a) McBride, J. M.; Merrill, R. A. J. Am. Chem. Soc. 1980, 102,
1723. (b) Berger, R.; Vinnand, G.; Olazcuaga, R.; Zahir, M. J. Non-Cryst.
Solids 1983, 54, 13. (c) Chateauneuf, J.; Lusztyk, J.; Ingold, K. U. J. Am.
Chem. Soc. 1988, 110, 2877. (d) Korth, H. G.; M u¨ ller, W.; Lusztyk, J.;
Ingold, K. U. Angew. Chem., Int. Ed. Engl. 1989, 28, 183.
(10) Chasar, D. W. US Patent 4439564, 1984; Chem. Abstr. 1984, 101,
130887.
(8) (a) Korth, H. G.; Lusztyk, J.; Ingold, K. U. J. Org. Chem. 1990, 55,
6
24, 3966. (b) Korth, H. G.; Lommes, P. Chem. Ber. 1992, 125, 2419.
562
Org. Lett., Vol. 6, No. 4, 2004

31
Table 1. δ ( P) (in ppm) and Yield (%) of Compounds 3
compda
R1
Ar
δ (31P)
yield (%)
b
3
a
OH
OEt
OEt
Ph
Ph
OEt
OEt
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
4-MeO-C6H4
3,5-diMe-C6H4
3,5-diMe-C6H4
47.33
43.8
59
24
37
48
37
29
40
trans-3b
cis-3b
trans-3c
cis-3c
trans-3d
cis-3d
42.77
53.62
61.65
44.88
43.91
a
The cis/trans descriptors indicate the relative arrangement of the
b
substituents R1 and Ar. Isolated.
Figure 2. Transient kinetic traces recorded at 340 nm following
55 nm laser excitation of a sample containing 2.5 mM of 3a in
not affected.12 The structural assignment of 3 was straight-
3
forward. The presence of the oxaphosphole moiety was
di-tert-butylperoxide/acetonitrile (50/50) under nitrogen (9) and
oxygen (O).
31
13
revealed by the large P, C coupling constants observed in
1
3
the C NMR spectra for the methine carbon attached to
1
phosphorus ( JPC ranging from 78.1 to 123.2 Hz) and the
The growth of the radical signal reflects the hydrogen
abstraction process (k ) and other forms of decay of tert-
2
butoxyl radicals (k ), such as reaction with the solvent and
0
â-cleavage. The experimental rate constant for the growth
C
ipso carbon adjacent to the oxygen atom and linked to the
t
3
Bu group ( JPC ranging from 6 to 9.6 Hz). The relative
configuration of the stereoisomers was readily deduced from
the NOEs observed in the 2D gNOESY spectra. Thus, the
ortho protons of the P-phenyl ring of trans-3c and cis-3c
correlate, respectively, with the methine proton at δ 4.53
is given by eq 3 in Scheme 2.
2
4
6
ppm (dt, JPH 8.1, JHH ) JHH 0.9 Hz) and the ortho pro-
3
tons of the p-methoxy substituent at δ 6.78 ppm (dd, JHH
Scheme 2. H-Abstraction Process by tert-Butoxyl Radicals
)
7.8 Hz).
Laser flash photolysis (λ ) 355 nm) of di-tert-butyl
peroxide in deaerated acetonitrile (50% v/v) in the presence
of 3a (2.5 mM) were carried out in order to generate the
corresponding benzylic radical and to study its reactivity with
1
3
oxygen. The resulting transient species showed one strong
UV band with maximum at 350 nm and a less intense broad
band with maximum in the visible at 580 nm (Figure 1A).
For comparison, the transient absorption spectrum obtained
upon photolysis of di-tert-butyl peroxide in the presence of
HP-136 in the same solvent is shown in Figure 1B. In the
presence of oxygen, the rates of growth and decay of the
oxaphosphole oxide radical (4a) were essentially the same
as under nitrogen, indicating a low reactivity toward oxygen
Accurate measurements of the rate constant for the
hydrogen abstraction process could not be done due to the
poor solubility of the phospholane oxides, which prevented
to obtain kinetic data at different concentrations. Then, the
efficiency of benzylic radical formation from 3a was esti-
mated by comparison with HP-136, using the same concen-
tration for both compounds. Figure 3 shows the transient
kinetic traces at the corresponding UV maxima obtained upon
laser excitation of the peroxide in the presence of 2.5 mM
solutions of 3a or HP-136.
1
4
(Figure 2). These data suggest that the phosphonyl group in
radical 4a provides a stability to the benzylic radical similar
to that of the carbonyl group in HP-136.
The same types of studies were carried out with both dia-
stereomers of compounds 3b-d. For all of them, the
generated radicals exhibited similar transient absorption
spectrum as that obtained from 3a; oxygen did not produce
any appreciable change in the growth or decay rate of these
radicals. However, comparison of the transient kinetic traces
recorded at 360 nm for each diastereomeric pair at the same
concentration revealed important differences in the relative
absorbances (see Figure 4 for cis-3b and trans-3b as an
example). It should be taken into account that, as mentioned
above, the growth of the signal reflects not only the hydrogen
atom abstraction by tert-butoxyl radical from the benzylic
position, but also other forms of decay of this radical. Hence,
this fact evidences a marked dependence of the hydrogen
(
11) (a) Ivanov, B. E.; Ageeva, A. B. IzV. Akad. Nauk SSSR, Ser. Khim.
1
967, 226; Chem. Abstr. 1967, 67, 11538. (b) Sidky, M. M.; El-Kateb, A.
A.; Hennawy, I. T. Phosphorus Sulfur Silicon 1981, 10, 343. (c) Chasar,
D. W. J. Org. Chem. 1983, 48, 4768. (d) Nifant’ev, E. E.; Kukhareva, T.
S.; Popkova, T. N.; Bekker, A. R. Zh. Org. Khim. 1987, 57, 2003; Chem.
Abstr. 1988, 109, 129113. (e) Gross, H.; Costisella, B.; Ozegowski, S.;
Keitel, I.; Forner, K. Phosphorus Sulfur Silicon 1993, 84, 121. (f) Gorg,
M.; Dieckbreder, U.; Schoth, R.-M.; Kadyrov, A. A.; Roschenthaler, G..-
V. Phosphorus Sulfur Silicon 1997, 124-125, 419. (g) Zhou, J.; Qiu, Y.
G.; Feng, K. S.; Chen, R. Y. Synthesis 1999, 234.
(12) Mukhametov, F. S.; Korshin, E.; Korshunov, R. L.; Efremov, Y.
Y.; Zyablikova, T. A. Zh. Org. Khim. 1986, 56, 1781; Chem. Abstr. 1987,
1
07, 576105.
13) Paul, H.; Small, R. D.; Scaiano, J. C. J. Am. Chem. Soc. 1978, 100,
520.
14) (a) Lohray, B. B.; Kumar, C. V.; Das, P. K.; George, M. V. J. Am.
(
4
(
Chem. Soc. 1984, 106, 7352. (b) Davis, H. F.; Lohray, B. B.; Gopidas, K.
R.; Kumar, C. V.; Das, P. K.; George, M. V. J. Org. Chem. 1985, 50,
685.
3
Org. Lett., Vol. 6, No. 4, 2004
563

Figure 4. Transient kinetic traces recorded at 360 nm following
55 nm laser excitation of a sample containing 7.2 mM of cis-3b
2) and trans-3b ([) in di-tert-butylperoxide/acetonitrile (50/50)
Figure 3. Transient kinetic traces recorded at the corresponding
maxima following 355 nm laser excitation of a sample containing
3
(
2.5 mM of 3a (4, at 355 nm) and HP-136 (b, at 340 nm) in di-
under nitrogen.
tert-butylperoxide/ acetonitrile (50/50) under nitrogen.
Acknowledgment. We thank Generalitat Valenciana, the
Spanish Government, and the European Union (Grant Nos.
BQU2001-2725 and BQU2002-00377 and FEDER project
FD97-1651) as well as the MECD (pos-doctoral fellowship
to R.E.G) for generous support of this work. We also thank
Ciba Specialty Chemicals for the samples of HP-136.
abstraction rate on the substrate configuration. In all cases,
the cis-stereoisomer showed the higher efficiency for benzylic
radical formation (between 4 and 10 times higher than that
of the trans-stereoisomer). A possible explanation could be
a favored hydrogen abstraction from the cis-stereoisomer due
to stabilization of the transition state by interaction between
the developing radical center and the PdO bond. Studies
are in progress in order to gain further insight into this effect.
Supporting Information Available: Synthetic procedures
and characterization for the preparation of heterocycles 3,
transient absorption spectra (for cis-3b, trans-3b, and cis-
In summary, comparison of the behavior of HP-136 and
3a toward tert-butoxyl radicals and the reactivity of the
generated benzylic radicals has demonstrated the suitability
of 3a as precursor of stabilized C-centered radicals, a
property associated with antioxidant potential. Using both
diasteromers of benzo[d]-1,2-oxaphosphole 2-oxides a dra-
matic stereodifferentiation in the hydrogen abstraction ef-
ficiency has been revealed.
3
d), and transient kinetic traces (for cis-3c, trans-3c). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL036345E
564
Org. Lett., Vol. 6, No. 4, 2004