Reductive dehalogenation and dehalogenative sulfonation of phenols and heteroaromatics with sodium sulfite in an aqueous medium

Article abstract of DOI:10.1039/c9gc00467j

Prototropic tautomerism was used as a tool for the reductive dehalogenation of (hetero)aryl bromides and iodides, or dehalogenative sulfonation of (hetero)aryl chlorides and fluorides, using sodium sulfite as the sole reagent in an aqueous medium. This protocol does not require a metal or phase transfer catalyst and avoids using organic solvent as the reaction medium. This method is especially suitable for substrates that readily tautomerize (such as 2-or 4-halogenated aminophenols and 4-halogenated resorcinols), for which dehalogenation or sulfonation proceeds under mild reaction conditions (≤60 °C). As sodium sulfite is an inexpensive, safe, and environmentally less hazardous reagent, this method has at least three potential applications: (i) in the deprotection of halogens as protecting groups, using sodium sulfite as a reducing agent; (ii) in the sulfonation of aromatic halides under mild reaction conditions avoiding hazardous and corrosive reagents/solvents; and (iii) in the transformation of toxic halogenated aromatics into less harmful compounds.

Full text of DOI:10.1039/c9gc00467j

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Received 00th January 20xx,
Reductive dehalogenation and dehalogenative sulfonation of
phenols and heteroaromatics with sodium sulfite in an aqueous
medium
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Monika Tomanová, Lukáš Jedinák and Petr Cankař *
Prototropic tautomerism was used as a tool for the reductive dehalogenation of (hetero)aryl bromides and iodides, or
dehalogenative sulfonation of (hetero)aryl chlorides and fluorides, using sodium sulfite as the sole reagent in an aqueous
medium. The protocol does not require a metal or phase transfer catalyst and avoids using organic solvent as the reaction
medium. This method is especially suitable for substrates that readily tautomerize (such as 2- or 4-halogenated
aminophenols, and 4-halogenated resorcinols), for which dehalogenation or sulfonation proceed under mild reaction
conditions (≤60 C). As sodium sulfite is an inexpensive, safe, and environmentally less hazardous reagent, this method has
at least three potential applications: (i) In the deprotection of halogens as protecting groups, using sodium sulfite as a
reducing agent; (ii) in the sulfonation of aromatic halides under mild reaction conditions avoiding hazardous and corrosive
reagents/solvents; and (iii) in the transformation of toxic halogenated aromatics into less harmful compounds.
for tautomerism-driven deiodination and, in a few cases,
debromination of phenols, anilines, and imidazoles.12 For
instance, Engman mimicked the enzymatic reduction of ortho-
Introduction
Aromatic carbon–halogen bonds are common functionalities
often utilized to increase the complexity of organic molecules,
especially in combination with cross-coupling chemistry. The
dehalogenation of aromatic halides is equally important and
deserving of research attention.1 This transformation allows
halogens to be used as protecting groups at certain positions
of an aromatic ring and persistent organic pollutants
containing carbon–halogen bonds to be converted into less
environmentally harmful compounds.2,3 Established methods
to remove halogens from aromatic rings rely on
environmentally harmful transition metal catalysts,4 radical tin
chemistry,5 or moisture-sensitive reductants.6 Alternative
methods have been developed to comply with the criteria of
green chemistry, but still require special synthetic reagents or
the use of organic solvents as a reaction medium.7–10
iodophenols using sodium hydrogen telluride.12a In another
inspiring report, Ramachandraiah reduced para-Br/I-phenol
and -Br/I-naphthol in
a
sulfite–bisulfate medium.12b,13
Despite having only five literature examples, three of which
afford only moderate yields, this method is among the
greenest approaches to reducing carbon–halogen bonds in
aromatic compounds. Owing to the limited number of truly
green dehalogenations methods, we sought to develop a
protocol that would enable the reduction of carbon–halogen
bonds using environmentally less hazardous reagents in an
aqueous medium.
Results and discussion
We initially screened the reduction of 4-bromophenol 1 to
phenol 2 using various sulfur-based reducing agents (NaSEt,
Na2S2O3, Na2S, and Na2SO3) alone or in a combination with
additives (NaI, NaOAc, K2CO3, KOH, and KHSO4). The results are
summarized in Table 1. The experiments were conducted in a
microwave reactor at 130 C.14 Sodium sulfite gave the best
result among the tested reducing agents (entries 1–4), leading
to quantitative conversion of 4-bromophenol 1 to phenol 2
without any detectable side products. The various additives,
including KHSO4, had negative (entries 5–7) or insignificant
In palladium-catalysed cross-coupling chemistry, the undesired
dehalogenation of NH-unprotected halogenated pyrazoles has
been observed and attributed to base-mediated
tautomerism.11 This finding led to the question of whether
halogen atoms can be removed from a broader range of
(hetero)aromatic substrates based on a mechanism involving
prototropic tautomerism. Some literature precedence exists
a. Department of Organic Chemistry, Palacký University, 17. Listopadu 1192/12,
77146, Olomouc, Czech Republic, E-mail: petr.cankar@upol.cz.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1 Optimization of the reaction conditions
and widely used fire retardant tetrabromobisphenol A 11,3f
with all four C–Br bonds reduced to C–H bonds, affording
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DOI: 10.1039/C9GC00467J
bisphenol 32 in 80% yield (entry 10).
Brominated thiophenol 12, aniline 13, and anilide 14 did not
react (entries 11–13), presumably owing to a lower tendency
to undergo prototropic tautomerization under the reaction
conditions. Furthermore, no reaction was observed for O-
methylated iodophenol 15 (entry 14).
The debromination of naphthol 16 was complicated by the
formation of bis-, tris-, and tetra-naphthol impurities, with
product 37 isolated in a lower yield (60%, entry 15). Both
iodine atoms in the phenolic part of L-thyroxine 17 were
reduced regioselectively, with iodides in the phenylether
portion remaining untouched to afford compound 38 in 92%
yield (entry 16).
Aminophenols 18 and 19 underwent facile debromination in
high yields, even at 60 C (entries 17 and 18). Remarkably, 4-
bromoresorcinol 20 afforded resorcinol 40 in 96% yield at
room
temperature
(entry
19).
Unexpectedly,
4-
effects (entry 8 and 9) on the reaction outcome. With
optimized conditions in hand using sodium sulfite (entry 4),
the scope and limitations were investigated using various
halogenated aromatic (Table 2) and heteroaromatic
compounds (Table 3). However, as the substrates showed
different reactivity, the conditions were changed for each
substrate individually (amount of sodium sulfite, reaction
temperature, and reaction time). Generally, reactions
requiring temperatures of ≥100 C were performed under
microwave irradiation, while conductive or no heating was
applied for lower reaction temperatures.15
chlororesorcinol 21 did not produce resorcinol 40, but
afforded a mixture of sulfonic acids 41 and 42. The ratio of 41
and 42 was dependent on the reaction temperature, with
sulfonic acid 41 preferred at 130 C (entry 20, 41/42 = 89:11),
while the ratio dropped to 59:41 at room temperature (entry
21). Sulfonic acid 41 was selectively obtained upon treatment
of 4-fluororesorcinol 22 with Na2SO3 at room temperature
after 14 days (entry 22). However, at 130 C, isomeric sulfonic
acid 42 was the major product (entry 23, 41/42 = 11:89). Two
meta-oriented hydroxyl groups with respect to the bromine
substituent (5-bromoresorcinol 23, entry 24), or 1,4-OH
substituted hydroquinone 24 (entry 25),3e led to the
unexpected formation of sulfonic acids 42 and 43, respectively.
Finally, derivatives of natural polyphenols 2517 and 2618 were
smoothly debrominated under mild conditions, yielding
quercetin 44 (entry 26) and resveratrol 45 (entry 27),
respectively.
Halogenated aromatics 1 and 3–26 were subjected to the
reaction with sodium sulfite in water, as shown in Table 2. 4-
Bromophenol 1 was reduced at 130 C, affording phenol 2 in
88% isolated yield (entry 1). 4-Iodophenol 3 was deiodinated
at a slightly lower temperature (100 C) to give phenol 2 in
91% yield (entry 2).16 2-Bromophenol 4 gave an identical yield
to 4-bromophenol 1 using the same reaction temperature and
time (entry 3). 2,4,6-Tribromophenol 5 required a slightly
prolonged reaction time for the complete reduction of all
three C–Br bonds (entry 4). Compound 6, bearing one ortho-
methyl substituent with respect to the bromine substituent,
showed a similar reactivity to 4-bromophenol 1 (entry 5), while
phenol 7, bearing two ortho-methyl substituents with respect
to the bromine substituent, showed increased reactivity, and
was, therefore, reduced at a lower temperature (100 C, entry
6). In contrast, two ortho-substituted methyl groups with
respect to the phenolic hydroxyl group slightly decreased the
reactivity, resulting in a longer reaction time (entry 7). The
reduction of isopropyl analogue 9 to propofol 30 was
completely inhibited (entry 8). The carboxyl group of phenol
10 had no effect on the reactivity (entry 9) and was
presumably deprotonated under the reaction conditions,
which would hinder the electron-withdrawing effect. Sodium
sulfite was successfully applied to the debromination of toxic
Halogenated heteroaromatics 46–59 were subjected to the
reaction with sodium sulfite in water, as shown in Table 3.
Pyrazoles 46–49 were dehalogenated in yields exceeding 90%
(entries 1–4). As expected, iodopyrazoles were more reactive
than bromopyrazoles, requiring lower temperatures or shorter
reaction times. No reaction was observed for N-methylated
iodopyrazole 50 (entry 5). Both possible regioisomers of
monobrominated imidazole 51 (C4–Br) and 52 (C2–Br) were
reduced to imidazole 63 (entries 6 and 7). The reduction of
imidazole C2–Br proceeded at a lower temperature compared
with imidazole C4–Br. This difference in reactivity was utilized
in the selective reduction of 2,4-dibromo-1H-imidazole 53,
which afforded 4-bromo-1H-imidazole 51 (entry 8).
Brominated benzimidazole 54 gave the expected product of C–
Br reduction (64) in 92% yield. Scaling up the experiment (~1 g
of 54), and applying either microwave or conductive heating
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Table 2. Scope of halogenated aromatics
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afforded equivalent results (entry 9). Chlorinated
benzimidazole 55 yielded sulfonic acid 65 instead of reduced
Table 3 Scope of halogenated aromatics.
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DOI: 10.1039/C9GC00467J
benzimidazole 64 (entry 10). Unexpectedly, the reduction of N-
methylated bromobenzimidazole 56 also proceeded
successfully (entry 11). Furthermore, the sulfonation of
chlorinated derivative 57 was successful (entry 12). Indole 58
was readily debrominated to compound 68 in 92% yield (entry
13). Finally, uracil derivative 59, capable of lactam/lactim
tautomerism, smoothly afforded debrominated product 69
(entry 14).
An example of a bromine substituent being used as a
protecting group is shown in Scheme 1. The chlorination of 4-
bromophenol 1 with N-chlorosuccinimide in water gave
intermediate 70, which was then reduced by Na2SO3. This one-
pot two-step process afforded 2,6-dichlorophenol 71 in 77%
yield.
Scheme 1. One-pot chlorination and debromination
Mechanistic study and proposal
In general, phenols and heterocycles bearing bromine or
iodine underwent dehalogenation upon treatment with
sodium sulfite (except 23 and 24, Table 2). A mechanism
explaining debromination and deiodination by Na2SO3 in water
is shown in Scheme 2. The reaction of 4-bromoresorcinol 20
with Na2SO3 at 40 C followed second-order kinetics, with both
20 and Na2SO3 appearing in the rate equation: (d[ArBr]/dt) =
k1[ArBr][Na2SO3], k1 = 5.65  104 M1 s1. This information,
together with the observed kinetic isotopic effect (k´H/D
=
5.09), indicated that prototropic tautomerism mediated by
Na2SO3 was the rate-determining step. Therefore, Na2SO3
plays a dual role; first, mediating proton transfer from
resorcinol 20 through anion 72 to give keto tautomer 73, and
second, abstracting bromine from tautomer 73 to produce
resorcinol 40 (path A). The latter step was fast and irreversible,
because highly reactive bromosulfonate 74 is rapidly
hydrolysed
to
sodium
bisulfate.
Alternatively,
thermodynamically more-stable diketo tautomer 75 is involved
in the mechanism if its formation from monoketo tautomer 73
is faster than bromine abstraction from 73 (path B).
The stereoelectronic effects of substituents on the aromatic
ring corresponded to the proposed tautomerism-driven
mechanistic pathway. 3-Aminophenols 18 and 19 and 3-
hydroxyphehols (resorcinols) 20, 25, and 26 underwent
debromination at much lower temperatures than other
substrates owing to the presence of a second amino or
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distinct mechanistic pathway, presumably via foVrimewaAtritoicnle Oonflinae
19
carbene intermediate (Table 3, entry D1O1I:).10.10A3c9c/oCr9dGiCn0g0ly4,67aJ
carbene mechanism was also involved in the debromination of
imidazoles 52 and 53 and benzimidazole 54 (see Table 3,
entries 7–9).
In contrast to (hetero)aryl bromides and iodides, chlorides and
fluorides afforded sulfonic acids instead of dehalogenated
products. The dehalogenative formation of sulfonic acids is
rationalized in Scheme 3, as exemplified by 4-fluororesorcinol
22 (see Table 2, entries 22 and 23). At room temperature,
sodium sulfite mediates the formation of kinetic 4H-tautomer
79, which subsequently participates in a SN1-like reaction (via
cation 80) with the sulfite anion, leading to sulfonate 81 (path
A). At 130 C, the reaction sequence most likely proceeds
through thermodynamic 2H-tautomer 82 (path B). The 1,4-
conjugate addition of sodium sulfite to thermodynamic 2H-
tautomer 82 gives adduct 83, which then affords sulfonate 84
after HF elimination. The dechlorinative sulfonation of 4-
chlororesorcinol 21 (Table 2, entries 20 and 21) was assumed
to occur via the 4H-tautomer, because the steric demand and
lower electronegativity of the chlorine atom did not favour
analogous tautomerism to the 2H-tautomer at a higher
temperature (Scheme 3). Consequently, the rate of the SN1-
like reaction of 21 was accelerated at 130 C to afford
predominantly sulfonic acid 41, while less-favourable sulfonic
acid 42 (Table 2, entry 20) was likely to form via a competitive
Scheme 2 Kinetic study and proposed mechanism.
addition–elimination mechanism through
a
kinetic or
thermodynamic tautomer. This competitive mechanism was
comparable to the SN1-like reaction at room temperature, but
with only the kinetic tautomer involved (Table 2, entry 21). In
contrast, the sulfonation of chlorinated benzimidazole 55 and
its N-methyl analogue 57 occurred via SNAr (Table 3, entries 10
and 12).
Figure 2 Steric effects on the dehalogenation.
hydroxyl functionality that effectively shifted the equilibrium
toward the reactive keto tautomers. Steric hindrance around
the C–Br bond of phenol 7, caused by two ortho-methyl
substituents, had a slightly positive effect on the reactivity,
resulting in a lower reaction temperature compared with
structurally related phenols. In contrast, steric hindrance
around the phenolic hydroxyl groups in compounds 8 and 9
had the opposite effect (see Table 2, entries 6–8). This
phenomenon can be attributed to the relative stability of the
keto tautomers of compounds 7–9 (Figure 1). Steric hindrance
around C4–Br is released when C4 adopts sp3 hybridization, as
shown in keto tautomer 76. In contrast, keto tautomers 77 and
78 experienced increased steric hindrance around the C1–O
bond compared with the corresponding enol forms 8 and 9.
This resulted in lower population of the keto tautomers and, as
a consequence, the reactivity of phenols 8 and 9 being
decreased or completely diminished.
Scheme 3 Defluorinative sulfonation of 4-fluororesorcinol 22.
There were two exceptions in which the addition–elimination
mechanism accounted for the unexpected sulfonation of
bromophenols (see Table 2, entries 24 and 25). First, none of
the tautomers of 5-bromoresorcinol 23 (85–87) allowed
bromine abstraction by Na2SO3 from the sp3-hybridized carbon
atom, which explained why the conjugated nucleophilic
addition of sulfite was favoured over C–Br reduction to C–H
(Scheme 4). Second, the reaction of sodium sulfite with
hydroquinone 24 most likely proceeded through 4H-tautomer
Heterocycles capable of annular or lactam–lactim tautomerism
underwent debromination or deiodination in a similar fashion
to phenols. Unprotected NH or OH functionalities were critical
for the reactivity of both heterocycles and phenols, as
demonstrated by the unreactivity of O/N-methylated
derivatives 15 and 50 (see entry 14 in Table 2 and entry 5 in
Table 3). Therefore, the successful debromination of N-
methylated benzimidazole 56 must have proceeded through a
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88 rather than 2H-tautomer 89 (Scheme 5). As bromine chlorination with N-chlorosuccinimide and debromination with
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abstraction from the sp2-hybridized carbon atom of tautomer sodium sulfite in an aqueous medium. DTOhIi:s10o.1n0e3-9p/oCt9GrCe0a0c4ti6o7nJ
88 was unfavourable, 1,4-addition led to adduct 90. Attempts demonstrated that bromine can be used as a temporary
to isolate intermediate 91 failed, because it underwent a protecting group and sodium sulfite as a deprotecting agent.
further addition–elimination sequence with the sulfite to yield Furthermore, the method allowed the transformation of
disulfonate 92.
halogenated pollutants into less harmful compounds, as
shown in the reductive debromination of toxic fire retardant
tetrabromobisphenol A 11 and debrominative sulfonation of
2,5-dibromohydroquinone 24, an unintended disinfectant
byproduct displaying embryotoxic properties.
Despite reductive dehalogenation based on prototropic
tautomerism having already been suggested for several
biologically relevant phenols or imidazoles, this study
demonstrated the more comprehensive reactivity of sodium
sulfite with variously halogenated and structurally diverse
(hetero)aromatics. Prototropic tautomerism was found to be
essential for reactivity with sulfite (for most substrates) and
was the rate-determining factor from a kinetics perspective.
Scheme 4 Debrominative sulfonation of 5-bromoresorcinol 23.
Experimental
General protocol for the dehalogenation of (hetero)aromatics
A 10-mL reaction vessel equipped with a magnetic stir bar was
charged with aryl halide (0.5 mmol), anhydrous sodium sulfite
(amount specified for each compound), and demineralized
water (2.5 mL). Under conventional heating, the mixture was
stirred at ambient temperature or in a preheated oil bath in a
closed vessel for
a specified time. Under microwave
Scheme 5 Debrominative sulfonation of hydroquinone 24.
irradiation, the vessel containing reaction mixture was sealed,
premixed for 1 min with rapid stirring in a CEM Discover SP
microwave synthesizer, and then irradiated at a maximum
power of 150 W with simultaneous cooling using compressed
air (24 psi). When the desired temperature was reached
(ramping time, ~1 min), the power was automatically adjusted
to maintain the set reaction temperature for a specified time.
Finally, the vessel was cooled to approximately 40 C with
compressed air (cooling time, ~1 min). The workup procedures
for individual compounds are described in the supporting
information. Generally, hydrodehalogenated products were
obtained in sufficient purity after liquid–liquid extraction, with
no chromatographic purification required. Sulfonated products
were obtained after acidification with hydrochloric acid.
Conclusions
Sodium sulfite has been demonstrated as an inexpensive, safe,
and environmentally less hazardous reagent for the reductive
dehalogenation or dehalogenative sulfonation of (hetero)aryl
halides in an aqueous medium. The reactivity of
(hetero)arylhalides is directly proportional to their tendency to
tautomerize. A kinetic study showed that sodium sulfite played
a key role in the formation of a reactive tautomer (rate-
determining step), which subsequently participated in distinct
pathways to yield either dehalogenated or sulfonated
products. The outcome of a reaction was influenced by the
nature of the halogen atoms (Br and I afford dehalogenation,
while F and Cl afford sulfonation) and the structure of the
reactive tautomer. Sulfonation occurred regardless of the
halogen atom if a reactive tautomer possessed a halogen atom
bonded to an sp2-hybridized carbon. Outside of tautomerism-
driven
dehalogenation/sulfonation,
imidazoles
and
benzimidazoles bearing Br/Cl substituents at the C-2 position
underwent debromination via formation of
intermediate or dechlorinative sulfonation via SNAr.
a carbene
The potential of this method has been demonstrated in the
synthesis of 2,6-dichlorophenol 71, which was efficiently
prepared from phenol 1 in a two-step procedure employing
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
M.T. and L.J. contributed equally. This work was supported by the Operational Programme Enterprise and Innovations for
Competitiveness (grant CZ.01.1.02/0.0/0.0/15_019/0004431) and the internal Palacky University IGA grants (IGA_PrF_2018_29
and IGA_LF_2018_32).
Notes and references
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For dehalogenation using photoredox catalysis, see: (a) I. Ghosh, T. Ghosh, J. I. Bardagi and B. König, Science, 2014, 346, 725; (b)
J. D. Nguyen, E.M. D’Amato, J. M. R. Narayanam and C. R. J. Stephenson, Nat. Chem., 2012, 4, 854; (c) J. J. Devery, J. D. Nguyen,
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10 For dehalogenation using NHC-boran, see: (a) S.-H. Ueng, L. Fensterbank, E. Lacôte, M. Malacria and D. P. Curran, Org. Biomol.
Chem. , 2011, 9, 3415; (b) X. Pan, E. Lacôte, J. Lalevée and D. P. Curran, J. Am. Chem. Soc., 2012, 134, 5569.
11 L. Jedinák, R. Zátopková, H. Zemánková, A. Šustková and P. Cankař, J. Org. Chem., 2017, 82, 157.
12 For dehalogenation by tautomerism, see: (a) A. A. Vasil´ev and L. Engman, J. Org. Chem., 1998, 63, 3911; (b) S. Adimurthy and G.
Ramachandraiah, Tetrahedron Lett., 2004, 45, 5251; (c) E. R. Goldberg, L. A. Cohen, Bioorg. Chem., 1993, 21, 41; (d) F.
Effenberger and P. Menzel, Angew. Chem. Int. Ed., 1971, 10, 493; (e) K. Raja and G. Mugesh, Angew. Chem. Int. Ed., 2015, 54,
7674; (f) E. J. O´Bara, R. B. Balsley and I. Starer, J. Org. Chem., 1970, 35, 16; (g) R. R. Talekar, G. S. Chen, S.-Y. Lai and J.-W. Chern,
J. Org. Chem., 2005, 70, 8590.
13 Aqueous sodium sulfite was previously used for reductive dehalogenation of polyhalogenated hydrocarbons: C. C. Dudman, CA.
Pat., 2074285A1, 1993.
14 Further studies regarding optimization of the reaction temperature and the type of heating are included in the Supporting
Information file.
15 Dehalogenation was not promoted by non-thermal microwave effects, as demonstrated on the hydrodebromination of
benzimidazole 54 (Table 3). For discussion on the non-thermal microwave effects, see: M. A. Herrero, J. M. Kremsner and C. O.
Kappe, J. Org. Chem., 2008, 73, 36.
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16 4-Chlorophenol did not react with aqueous sodium sulfite, even at 170 C.
View Article Online
17 M. Peng, F. Liu, X. Feng, F. Yang and X. Yang, Asian J. Chem., 2014, 26, 4701.
18 X.-Z. Li, X. Wei, Ch.-J. Zhang, X.-L. Jin, J.-J. Tang, G.-J. Fan and B. Zhou, Food Chem., 2012, 135, 1239.
DOI: 10.1039/C9GC00467J
19 For the dehalogenation of 2-haloimidazoles via a carbene intermediate, see: (a) K. L. Kirk, W. Nagai and L. A. Cohen, J. Am. Chem.
Soc., 1973, 95, 8389; (b) R. S. Phillips and L. A. Cohen, J. Am. Chem. Soc., 1986, 108, 2023.
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