Electron-transfer-induced reductive cleavage of chlorinated aryloxyalkanoic acids

Article abstract of DOI:10.1016/j.tet.2011.03.057

We investigated the degradation of chlorinated herbicides, with an aryloxyalkanoic acid skeleton, under reductive electron transfer reaction conditions. Although Li and Na metals proved useless, activated forms of these metals, either their soluble naphthalene radical anions or 1,2-diarylethane dianions, promoted the degradation of the starting materials to various extents. Indeed, lithium naphthalenide promoted both extensive dehalogenation and dealkylation of chlorinated aryloxyalkanoic acids, with formation of the corresponding phenols as the main reaction products. In contrast, the employment of 1,2-diphenyl-1,2-disodioethane as a reducing agent led, in most examples, to the chemoselective recovery of the corresponding dechlorinated acids.

Full text of DOI:10.1016/j.tet.2011.03.057

Tetrahedron 67 (2011) 3360e3362
Contents lists available at ScienceDirect
Tetrahedron
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Electron-transfer-induced reductive cleavage of chlorinated aryloxyalkanoic acids
*
Ugo Azzena , Mario Pittalis
ꢀ
Dipartimento di Chimica, Universita di Sassari, via Vienna 2, I-07100, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
We investigated the degradation of chlorinated herbicides, with an aryloxyalkanoic acid skeleton, under
reductive electron transfer reaction conditions. Although Li and Na metals proved useless, activated
forms of these metals, either their soluble naphthalene radical anions or 1,2-diarylethane dianions,
promoted the degradation of the starting materials to various extents. Indeed, lithium naphthalenide
promoted both extensive dehalogenation and dealkylation of chlorinated aryloxyalkanoic acids, with
formation of the corresponding phenols as the main reaction products. In contrast, the employment
of 1,2-diphenyl-1,2-disodioethane as a reducing agent led, in most examples, to the chemoselective
recovery of the corresponding dechlorinated acids.
Received 16 January 2011
Received in revised form 28 February 2011
Accepted 21 March 2011
Available online 26 March 2011
Keywords:
Aryloxyalkanoic acid
Chlorinated herbicide
Electron transfer
Hydrodealkylation
Hydrodehalogenation
Reduction
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Several chlorinated aryloxyalkanoic acids are extensively used as
herbicides, with 2,4-dichlorophenoxyacetic acid (2,4-D)1 being one of
the most widely used pesticide in the world. Furthermore, an ap-
proximately 1:1 mixture of 2,4-D and 2,4,5-trichlorophenoxyacetic
acid (2,4,5-T), the latter in the form of its n-butyl ester, was extensively
used as a general purpose herbicide for defoliation and crop de-
struction during the Vietnam War.2 Due to their toxicity and envi-
ronmentalhazard, severalmethodologies have beenproposedfortheir
degradation, including photocatalyzed oxidation,3 electrocatalytic
reduction4 or combustion,5 and catalyzed hydrodechlorination.6
Although the employment of alkali metals as Single Electron Transfer
(SET) reducing agents was successfully applied to the degradation of
several chlorinated persistent aromatic pollutants,7 to the best of our
knowledge no report concerns the application of such a procedure to
the hydrodehalogenation of chlorinated aryloxyalkanoic acids.
We previously reported on the successful application of the
reductive dehalogenation to halogenated benzoic8 acids, using 1,2-
diaryl-1,2-disodioethanes9 in THF as highly activated forms of Na
metal, functioning under homogeneous and mild reaction condi-
tions. Following our interest in the field, we now wish to report the
results of an investigation aimed to highlight the reductive degra-
dation of chlorinated aryloxyalkanoic acids under electron transfer
reaction conditions.
We first investigated the reductive degradation of a series of
chlorinated aryloxyacetic acids widely employed as herbicides.
These include 4-chlorophenoxyacetic acid (4-CPA, 1a), 2-methyl-4-
chlorophenoxyacetic acid (MCPA, 1b), 2,4-D (1c) and 2,4,5-T (1d).
Their reactivity was investigated towards different SET re-
ducing agents, including Li and Na metals, Li naphthalenide (LiN,
2a), Na naphthalenide (NaN, 2b), 1,2-dilithio-1,2-diphenylethane
(1,2-dilithiostilbene, DLS, 3a), 1,2-diphenyl-1,2-disodioethane
(1,2-disodiostilbene, DSS, 3b) and 1,2-disodiostilbene-1,2,3,4-
tetraphenylethane (DSTPE, 3c). Concerning the different activated
forms of the alkali metals employed in this work, it is worth noting
that radical anions 2a and 2b are one-electron donors, whilst the
vic-diorganometals 3aec are two-electrons donor reagents.
The reaction of one of these reducing agents with a halogenated
carboxylic acid can be foreseen to give rise to deprotonation of the
carboxylic moiety as well as to different reductive cleavage path-
ways, i.e., dehalogenation (CeCl bond cleavage) and dealkylation
(aliphatic CeO bond cleavage).10,11 The deprotonation reaction
should require a 1:1 molar ratio of acid to alkali metal (or to radical
anion), whilst the same reaction should require a 1:0.5 molar ratio
of acid to dianion. In contrast, reductive cleavage of a carbon-
eheteroatom bond could require an acid to alkali metal (or radical
anion) molar ratio reaching 1:2, or an acid to vic-diorganometal
molar ratio reaching 1:1.8,10 Accordingly, we run most reactions
with an acid to reducing agent molar ratio chosen in order to allow
all the above cited reaction pathways to go to completion.
* Corresponding author. Tel.: þ39 079229549; fax: þ39 079229559; e-mail
address: ugo@uniss.it (U. Azzena).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.057

U. Azzena, M. Pittalis / Tetrahedron 67 (2011) 3360e3362
3361
All reactions were run in dry THF under a N2 atmosphere, by
adding solutions of the different halogenated aryloxyalkanoic acids
to suspensions (for Li and Na metals) or solutions (for radical anions
and dianions) of the reducing agent, cooled to 0 ꢀC. No attempt was
made to determine the minimum reaction time required for the
reaction to go to completion. Accordingly, reaction mixtures were
stirred and allowed to warm to rt for 12 h, and quenched with H2O.
Acidic reaction products were recovered by acidifying the aqueous
phase with 1 N HCl; this work-up led to a mass recovery typically
ꢁ 90%, and crude mixtures were analyzed by 1H NMR spectroscopy.
The results are reported in Table 1 (Scheme 1).
not reported in Table 1), thus suggesting that some component(s) of
the reaction medium behaved as proton (or hydrogen atom) donor
(s) towards some reactive dechlorinated intermediate(s).12
Finally, and in agreement with the relatively low reducing
properties of this reagent,9 the reduction of 1a with DSTPE afforded
relatively low conversion of the starting material into the corre-
sponding dechlorinated product, 4a (Table 1, entry 8).
We further investigated the reduction of MCPA, 1b, 2,4-D,1c and
2,4,5-T, 1d, under similar reaction conditions. In agreement with
the previous results, the employment of DSS, 3b, as a SET reducing
agent, allowed their highly regioselective conversion into the cor-
responding dehalogenated aryloxyacetic acids (Table 1, entries 9, 13
and 14). Moreover, the reduction of 2,4-D, 1c, with LiN, 2a, further
highlighted the ability of the last reagent to promote both the
dehalogenation and the dealkylation reaction (Table 1, entry 12).
Furthermore, it is worth noting that Li and Na alone proved useless
in the degradation of the dichloro-substituted acid 1c (Table 1,
entries 10 and 11).
Finally, we investigated the reductive cleavage of two chlori-
nated herbicides possessing a somewhat different aryloxyalkanoic
skeleton, i.e., 2-[4-chlorophenoxy]propionic acid (4-CPP), 1e, and
4-[4-chloro-2-methylphenoxy]butanonic acid (4-CPB), 1f, employing
DSS, 3b, as a reducing agent.
Scheme 1. Reaction of chlorophenoxyacetic acids, 1aed, with various SET reagents. 1a,
R¼X1¼X2¼H; 1b, R¼CH3, X1¼X2¼H; 1c, R¼X1¼H, X2¼Cl; 1d, R¼H, X1¼X2¼Cl; 4a, 5a,
R¼H; 4b, 5b, R¼CH3; M¼Li or Na; 2 and 3, see Table 1 and text.
Under appropriate conditions, i.e., with an acid to reducing
agent molar ratio of 2:1 and within relatively short reaction time, it
was possible to achieve the highly regioselective dehalogenation of
the aryloxypropionic acid 1e; at variance with this result the ary-
loxybutanoic acid 1f underwent dehalogenation as well as deal-
kylation with particularly ease (Scheme 2).
Table 1
Reductions of acids 1 with various SET reagentsa
Entry
Substrate
SET reagent
Acid/SET
reagentb
Product distributionc,d
1 (%)
4 (%)
5 (%)
1
2
3
4
5
6
7
8
4-CPA, 1a
4-CPA, 1a
4-CPA, 1a
4-CPA, 1a
4-CPA, 1a
4-CPA, 1a
4-CPA, 1a
4-CPA, 1a
MCPA, 1b
2,4-D, 1c
2,4-D, 1c
2,4-D, 1c
2,4-D, 1c
2,4,5-T, 1d
Li
Na
1:5
1:5
1:5
1:6.5
1:5
1:2.5
1:2.5
1:2.5
1:2.5
1:7.0
1:7.0
1:8.0
1:3.5
1:4.5
1a, >95
1a, >95
d
d
d
d
d
LiN, 2a
LiN, 2a
NaN, 2b
DLS, 3a
DSS, 3b
DSTPE, 3c
DSS, 3b
Li
4a, 22
4a, 8
5a, 78
5a, 92
5a, 44
5a, 43
d
d
d
4a, 56
4a, 57
4a, >95
4a, 40
4b, >95
d
d
d
1a, 60
d
d
9
d
10
11
12
13
14
1c, >95
1c, >95
d
d
Na
d
d
LiN, 2b
DSS, 3b
DSS, 3b
4a, 16
4a, >95
4a, >95
5a, 84
d
d
d
d
a
All reactions were run in dry THF, under N2, for 12 h at rt.
Molar ratio.
b
c
Scheme 2. Reduction of 2-[4-chlorophenoxy]propionic acid, 1e, and 4-[4-chloro-2-
methylphenoxy]butanoic acid, 1f, with DSS, 3b.
As determined by 1H NMR spectroscopic analyses of crude reaction mixtures.
d
Formation of minor amounts (<10%) of unidentified by-products was occa-
sionally observed.
3. Conclusions
The reactivity of 1a, taken as a model compound, was in-
vestigated in some detail. In agreement with previous results
obtained with halobenzoic acids,8 reaction of 1a with either Li or Na
metaldid not result in anycleavagereaction (Table 1, entries 1and 2).
In contrast, and depending on the relative amount of the re-
ducing agent, reaction of 1a with LiN, 2a, resulted in the quanti-
tative cleavage of the aromatic carbonechlorine bond, as well as in
the extensive cleavage of the aliphatic carboneoxygen bond (Table
1, entries 3 and 4). Comparable results were observed employing
NaN, 2b, as a reducing agent, although this reagent proved less
effective in promoting the dealkylation reaction (Table 1, entry 5).
Similar results were obtained in the reduction of 1a with the
corresponding dianionic derivative. Indeed, the reaction of 1a with
DLS, 3a, afforded an almost equimolar mixture of phenoxyacetic
acid, 4a, and phenol, 5a (Table 1, entry 6), whilst a similar reaction
employing its sodium analogue, 3b, as a reducing agent, regiose-
lectively afforded the product of cleavage of the carbonechlorine
bond (Table 1, entry 7).
The above reported results show that activation of Li or Na metal,
either in the form of their soluble naphthalene radical anions or 1,2-
diarylethane dianions, allows their employment in the reductive
degradation of chlorinated aryloxyalkanoic acids. Some of these
reagents are able to promote, besides the cleavage of aromatic car-
bonechlorine bonds, the reductive dealkylation of chlorophenoxy
herbicides. This observation is particularly interesting in the case of
aryloxyacetic acids, due to the known stability of this kind of ali-
phatic carboneoxygen bond underavariety of reaction conditions.13
In addition, the above reported results show that Li derivatives,
either the radical anion or the dianion, aremoreeffectiveas reducing
agents than the corresponding Na derivatives. Furthermore, the
lithium radical anion of naphthalene (LiN, 2a) proved more effective,
under the above reported set of reaction conditions, then the cor-
responding lithium dianion (DLS, 3a), and the same was true for the
couple NaN, 2b, and DSS, 3b. Accordingly, the choice of an appro-
priate SET reagent appears as a key step to obtain the reduction of
chlorinated aryloxyalkanoic acids either into the corresponding
dehalogenated carboxylic acids or phenols, thus disclosing an
approach not only to the degradation but also to the reuse of this
class of compounds.
Quenching the last reduction mixture with D2O did not lead to
the incorporation of deuterium on the aromatic ring (as de-
termined by 1H NMR spectroscopic analysis of the crude mixture,

3362
U. Azzena, M. Pittalis / Tetrahedron 67 (2011) 3360e3362
ꢀ
4. Experimental
organici persistenti’, and from the Universita di Sassari (Fondo di
Ateneo per la Ricerca) is gratefully acknowledged. M.P. acknowl-
edges financial support from the Regione Autonoma della Sardegna
(Italy), through the project ‘Promozione della Ricerca Scientifica e
dell’Innovazione Tecnologica in Sardegna’.
4.1. General
Starting materials were of the highest commercial quality and
were purified by distillation or recrystallization immediately prior
to use. THF was distilled from Na/K alloy under N2 immediately
prior to use. 1H NMR spectra were recorded at 300 MHz and 13C
NMR spectra were recorded at 75 MHz in DMSO-d6 (unless other-
wise indicated) on a Varian VXR 300 spectrometer. IR spectra were
recorded on an FT-IR Jacso 680 P. TLC analyses on Macherey-Nagel
silica gel pre-coated plastic sheets (0.20 mm).
Appendix. Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.03.057. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.2. Starting materials
References and notes
Aryloxyalkanoic acids 1aec are commercially available; ary-
loxyalkanoic acids 1d,14 and 1f15 were synthesized according to
a procedure described in Ref. 16, whilst 1e17 was synthesized
according to a procedure described in Ref. 18. Literature charac-
terization of acid 1f reports only its mp;15 accordingly, we wish to
report here a more complete characterization of this compound.
1. Acronyms of aryloxyalkanoic acid are taken from the Compendium of Pesticide
Common Names, http://www.alanwood.net/pesticides/class_herbicides.html.
2. Committee to Review the Health Effects in Vietnam Veterans on Exposure to
Herbicides, Division of Health Promotion and Disease Prevention, Institute of
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N. New J. Chem. 2003, 27, 836e843.
4.2.1. 4-[4-Chloro-2-methylphenoxy]butanoic acid, 1f. White pow-
der, mp¼100e102 ꢀC (CH2Cl2) (lit.15 mp¼101 ꢀC). Anal. Found: C,
57.64; H, 5.92; C11H13ClO3 requires: C, 57.78; H, 5.73%; IR (Nujol)
4. Tsyganok, A. I. Res. Chem. Intermed. 2006, 32, 357e372.
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; d 1.95 (2H, m, CH2), 2.13 (3H, s, CH3),
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2.39 (2H, t, J¼7.2 Hz, CH2), 3.97 (2H, t, J¼6.4 Hz, CH2), 6.91 (1H, d,
J¼8.8 Hz, ArH), 7.15e7.20 (2H, m, 2ꢃArH). 13C NMR (DMSO):
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0.2 M solutions of radical anions 2a19 and 2b,20 as well as of
dianions 3a,21 3b21 and 3c,22 in dry THF were prepared as already
described.
4.3. Reductive cleavage of chloronated aryloxyalkanoic acids
1aef. General procedure
To 10 mL of a 0.2 M solution of a SET reagent 2 or 3 (2 mmol),
cooled to 0 ꢀC, was added a solution of the appropriate arylox-
yalkanoic acid 1 (for the relative molar ratios, see Table 1), dissolved
in dry THF (5 mL). Reactions with Li or Na metal were run under
closely related reaction conditions, by adding solutions of the ap-
propriate aryloxyalkanoic acid 1 to suspension of the freshly cut
metal in dry THF.
Each mixture was vigorously stirred and allowed to reach rt for
12 h, after which time it was quenched by slow dropwise addition
of H2O (15 mL). The organic solvent was evaporated in vacuo and
the resulting mixture was extracted with CH2Cl2 (3ꢃ10 mL). The
aqueous phase was acidified with 1 N HCl, extracted with CH2Cl2
(3ꢃ10 mL), and the organic phases were collected, washed with
H2O (1ꢃ10 mL), brine (10 mL) and dried (Na2SO4). After evapora-
tion of the solvent, the resulting mixture was analyzed by 1H NMR
spectroscopy.
9. Azzena, U.; Pisano, L.; Antonello, S.; Maran, F. J. Org. Chem. 2009, 74, 8064e8070
and references therein.
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11. We did not observe evidences of competitive dealkoxylation reactions (aromatic
CeO bond cleavage, see Ref. 10).
12. The reductive cleavage of an aromatic carbonehalogen bond is usually con-
sidered to proceed via the intermediate formation of an aromatic radical, which
can be further reduced to the corresponding carbanion. See Ref. 8 and refer-
ences therein.
13. Mirk, D.; Waldvogel, S. R. Tetrahedron Lett. 2004, 45, 7911e7914 and references
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€
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Reaction products 4aec, 5a and 5b were characterized by
comparison with commercially available samples; aryloxybutanoic
acid 4d23 was characterized by comparison with literature data.23
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3892e3900.
Acknowledgements
23. Liao, J.; Tang, P.; Gschneider, D.; Maeyer, J. U.S. Patent US 2010/0015,088 A1, Jan.
21, 2010; 1H NMR spectrum and mp are also available via the internet on
Financial support from the Fondazione Banco di Sardegna
(Sassari, Italy), through the project ‘Dealogenazione di inquinanti
ReaxysÒ
.