Dehalogenation of functionalized alkyl halides in water at room temperature

Article abstract of DOI:10.1039/c4gc01733a

Alkyl bromides and chlorides can be reduced to the corresponding hydrocarbons utilizing zinc in the presence of an amine additive. The process takes place in water at ambient temperatures, enabled by a commercially available designer surfactant. The reaction medium can be readily recycled, and the amount of organic solvent invested for product isolation is minimal, leading to very low E Factors. This journal is

Full text of DOI:10.1039/c4gc01733a

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Dehalogenation of functionalized alkyl halides
in water at room temperature†
Cite this: DOI: 10.1039/c4gc01733a
Nicholas A. Isley, Matt S. Hageman and Bruce H. Lipshutz*
Received 6th September 2014,
Accepted 29th September 2014
Alkyl bromides and chlorides can be reduced to the corresponding hydrocarbons utilizing zinc in the
presence of an amine additive. The process takes place in water at ambient temperatures, enabled by a
commercially available designer surfactant. The reaction medium can be readily recycled, and the
amount of organic solvent invested for product isolation is minimal, leading to very low E Factors.
DOI: 10.1039/c4gc01733a
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Introduction
Methods for the reduction of carbon halogen bonds play an
indispensible role in organic synthesis. Reactions that count
on such processes, such as halocyclizations, or the reduction
of an alcohol via its halide derivative to its hydrocarbon oxi-
dation state, can be readily found in textbooks. These include
such classical approaches as use of tin hydride reagents, and
Grignard formation/protio-quenching.1 While some may be
applicable to mass reductions of environmental pollutants,
such as PCBs, clean, mild, and green reductions of halogen-
containing intermediates in highly functionalized systems
remains quite a challenge.2 More recent methods such as
photo-redox chemistry,3 while very efficient, relies on a pre-
cious metal, and super-stoichiometric amounts (i.e., 10 equiv.
each) of both i-Pr2NEt and formic acid to complete the cata-
lytic cycle, which adds considerably to the waste stream
despite its catalytic-in-metal nature. Perhaps the major draw-
back is the choice of solvent, as it must be carefully chosen to
minimize absorbance from the light source. This led to the
selection of DMF, a solvent with a questionable future due to
its environmental toxicity and health hazards associated with
its use.4 Other reagents such as NHC–borane complexes5 have
also been shown to facilitate halide reduction, but such a
process requires an additional equivalent of a trialkylborane or
AIBN and is applicable only to activated alkyl halides.
Scheme 1 Dehalogenation of alkyl halides utilizing zinc under micellar
catalysis using designer surfactant TPGS-750-M.
presence of nanomicelles composed of the commercially avail-
able designer surfactant TPGS-750-M (Scheme 1). The well-
known compatibility of zinc6 with a wide range of functional
groups is especially appealing and suggests that such an
approach should be broadly applicable. Given the already
aqueous nature of the reaction medium (0.5 M), workup only
requires a simple filtration through silica gel to remove zinc
and the surfactant from the reaction mixture (Scheme 1). In
some cases, only a slight excess of zinc (1.1 equiv.) is required,
plus a sub-stoichiometric amount of an amine salt to achieve
dehalogenation in high yields. This method generates a zinc
halide salt as by-product that, in principle, has commercial
value. Overall, the desired transformation is chemoselective,
takes place in the absence of organic solvent,7 and offers the
potential for recycling of the aqueous medium.
In this report we describe an especially straightforward,
cost effective, and green technology for hydrodehalogenation
of both activated and unactivated alkyl bromides, and acti-
vated chlorides, that takes place at room temperature in water
as the only medium. The reduction is mediated by inexpen-
sive, commercially available metallic zinc dust, enabled by the
Results and discussion
An initial screening of surfactants identified TPGS-750-M,8,9 as
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
CA 93106, USA. E-mail: lipshutz@chem.ucsb.edu
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR characterization data for all new compounds. See DOI: 10.1039/c4gc01733a
the preferred amphiphile in water. Given that it is an item of
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Scheme 3 Direct comparison of photoredox chemistry vs. micellar
catalysis.
Scheme 2 Dehalogenation of activated and unactivated alkyl halides.a
a Conditions: Zn0 (4 equiv.), TMEDA (2 equiv.), 2 wt % TPGS-750-M/H2O
(0.5 M), rt. b Zn0 (1.5 equiv.), NH4Cl (0.5 equiv.). c Zn0 (2 equiv.), NH4Cl (1
equiv.). d Zn0 (1.1 equiv.), NH4Cl (0.5 equiv.). e Too volatile to isolate.
f Ratio by GCMS analysis. g Required nanoparticle Zn0 for di-
dehalogenation.
Scheme 4 Reaction rate acceleration and lower loading of zinc using
NH4Cl in place of TMEDA.
commerce, it was used throughout the study.10 The combi-
nation of zinc dust, along with tetramethylethylenediamine
(TMEDA) in the pot, led to smooth dehalogenation. This result
was anticipated based on earlier studies involving in situ
organozinc halide formation, which in the presence of an aryl
halide and Pd catalyst, led to net Negishi-like couplings.11
Related copper-catalyzed conjugate additions12 in water, fol-
lowing an initial formation of an organozinc halide, was also
encouraging precedent.
As shown in Scheme 2, a variety of activated and unacti-
vated alkyl bromides was readily reduced under these con-
ditions. Tolerance of a considerable range of functional groups
was observed, as expected,11,12 and included pyridyl, indolyl,
esters, ketones, terminal alkynes, and aryl halides. Unactivated
alkyl chlorides appear to be nonresponsive to these con-
ditions, although activated cases are smoothly reduced at
room temperature (vide infra). As for a dihalocyclopropane,
attempted reduction in the absence of TPGS-750-M (i.e., “on
water”), afforded only 14% conversion, while 96% of this educt
was reduced after 8 h in the presence of the amphiphile, a
clear indication that micellar catalysis is involved in these
reductions.
can be achieved using zinc dust, while nanoparticle zinc was
effective for di-dehalogenation, affording 10.
Direct comparison with Ru-catalyzed photo-redox chemistry
involving both activated alkyl bromides and chlorides
illustrates the competitive nature of this aqueous micellar
approach.3 Thus, by using inexpensive zinc ($1.2 Zn/mol sub-
strate vs. $19.8 Ru/mol substrate), reliance on a precious-metal
catalyst is averted,13 as is a traditional extraction, typically
involving copious quantities of water to remove the DMF used
as solvent (Scheme 3). This is yet another case where micellar
catalysis can be not only a viable, but in fact highly attractive,
alternative to dipolar aprotic solvents.14
Activated alkyl chlorides were typically slower to reduce
compared with alkyl bromides, and so attempts were made to
improve reaction rates of these dehalogenations. Simply repla-
cing TMEDA with ammonium chloride led to a significant
acceleration in the rate of reduction (Scheme 4). As a bonus, it
also allowed a decrease in the amount of zinc to just over stoi-
chiometric levels.
With the newfound use of NH4Cl as an additive it was
thought that it could drastically reduce both the reaction times
and stoichiometry of zinc. These conditions were applied to
both unactivated and activated alkyl bromides (Scheme 2).
Unfortunately, replacement of TMEDA with NH4Cl was appli-
cable only to activated alkyl bromides, and required prolonged
reaction times. Both 1 and 3 were fully dehalogenated in the
presence of NH4Cl, but the former required 1.5 equiv. of Zn,
otherwise a moderate amount of homocoupling was observed.
Selection of the zinc used is another important parameter,
as zinc dust had the highest selectivity, while zinc powder
showed limited reactivity. Use of more costly and highly active
nano-sized zinc led to cleavage of ester groups, alkyne
reduction, and dehalogenation of aryl halides (see ESI† for
details). It is noteworthy that dehalogenation of the aryl
chloride or reduction of the ester was not observed for 2 when
nano-particle zinc was utilized. In the case of the dihalocyclo-
propyl system, reasonable selectivity for mono-dehalogeation
Low conversion was observed with unactivated cases
2
(Scheme 2) and 13 (Table 1, entry 1). Unactivated cases were
successively dehalogenated as the amount approached the
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Table 1 Evidence of pH dependence for reduction of unactivated alkyl
bromides with zinc
Entry
Zn (equiv.)
Additive (equiv.)
pH
Conv.a
Time (h)
1
2
3
4
5
2
2
3
1.1
2
NH4Cl (0.5)
NH4Cl (1.0)
NH4Cl (1.0)
NH4OH (0.5)
NH4OH (1.0)
4–5
4–5
4–5
7–8
7–8
13%
22%
78%
27%
58%
48
48
22b
22b
22b
a Reactions were run at rt; determined by GCMS of crude material. b No
additional conversion was observed after this period of time.
Scheme 6 E Factors associated with recycling of the reaction mixture.
waste, the E Factors (8.5 and then 6.4) are far lower than those
typically reported for reactions by the pharmaceutical and fine
chemicals industries.17 These numbers also compare favorably
with those from other academic labs directly involved in
related dehalogenation chemistry (see ESI†),3 although they
are merely illustrative of the potential economic as well
as environmental benefits to be realized from nanomicelle
technology.
Conclusions
In summary, an experimentally simple yet robust technology
has been developed for reductions of alkyl bromides and
chlorides containing a wide variety of potentially sensitive
functional groups under aqueous micellar conditions at room
Scheme 5 Reduction of TNP-470 under micellar conditions.
originally used 3 equivalents (Table 1, entry 3). Next, NH4OH temperature. A minimal amount of a single organic solvent is
was used instead to produce a more basic medium similar to all that need be invested in order to extract the desired
TMEDA. The trend suggests that less zinc can be utilized for product. Hence, the E Factors associated with these reductions
the dehalogenation of unactivated cases if conditions are basic are very low, and are suggestive of the savings to both the cost
(Table 1, compare entries 2 and 5).
of such reductions as well as the environment that might be
To demonstrate further the selectively and functional group anticipated by virtue of this chemistry.
compatibility of zinc under these micellar conditions,
TNP-470, a potent antiangiogenic inhibitor containing an
α-chloroamide15 was subjected to Zn-mediated reduction at
room temperature in the presence of ammonium chloride.
Experimental
General information
Selective dehalogenation was observed, affording the antici-
pated product 14 in good isolated yield (Scheme 5).
Unless otherwise noted, all reactions were performed under an
atmosphere of argon. All commercially available reagents were
used without further purification. A 2 wt% TPGS-750-M/H2O
solution was prepared by dissolving 4 g TPGS-750-M in 196 g
water (HPLC grade), followed by degassing with argon.
TPGS-750-M was made as previously described.8 TPGS-750-M
is also available commercially.10 Analytical thin layer chromato-
graphy (TLC) was performed using Silica Gel 60 F254 plates
(Merck, 0.25 mm thick). The developed chromatogram was
analyzed by UV lamp (254 nm). For non-UV active compounds
were visualized by aqueous potassium permanganate
(KMnO4), vanillin, or ninhydrin stain developed by heat with a
heat gun. Flash chromatography was performed in glass
The opportunity also exists to recycle these aqueous reac-
tion mixtures following an in-flask extraction with a single
organic solvent (EtOAc in this case). Using an α-chloro ester as
the educt, product
8 could be isolated in 90% yield
(Scheme 6). Addition of a second, different α-chloro ester to
the same aqueous reaction mixture afforded upon extraction
product 12 in 86% isolated yield. Using the minimum amount
of EtOAc in each of these product extractions, the calculated E
Factors, based solely on the use of organic solvent (which is
85–90% of organic waste) and which traditionally do not
include water, are very low (2.6 and 2.4, respectively).16 Even
with water (i.e., the reaction medium) included as eventual
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columns using Silica Flash® P60 (SiliCycle, 40–63 μm). GC-MS General procedure for recycling of the aqueous surfactant
data was recorded on a 5975C Mass Selective Detector, coupled solution
with a 7890A Gas Chromatograph (Agilent Technologies). As
After extraction of the desired product from the aqueous
capillary column a HP-5MS cross-linked 5% phenylmethylpoly-
phase, reuse of the surfactant solution was employed
siloxanediphenyl column (30 m × 0.250 mm, 0.25 micron,
by adding additional Zn (2 equiv.) to the flask. Next, NH4Cl
Agilent Technologies) was employed. Helium was used as
(0.5 equiv.) and 4-bromobenzyl 2-chloro-2-phenylacetate
carrier gas at a constant flow of 1 mL min−1. The following
(1.0 mmol) were added. The reaction was allowed to stir at rt
until complete. The product was extracted with EtOAc (350 μL
temperature program was used: 50 °C for 5 min; heating rate
20 °C min−1; 300 °C for 20 min; injection temperature 250 °C;
+ 350 μL). The organic solvent was evaporated via rotary evap-
detection temperature 280 °C. H and 13C NMR were recorded
1
oration. The crude product was purified by silica gel column
at 22 °C on a Varian UNITY INOVA 400 MHz, 500 MHz, or
chromatography (eluent: gradient from 1 to 10% EtOAc–
1
600 MHz. Chemical shifts in H NMR spectra are reported in
hexanes) to provide the desired compound as a colorless oil
(262 mg, 86% yield).
parts per million (ppm) on the δ scale from an internal stan-
dard of residual chloroform (7.26 or 7.27 ppm). Data are
reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, p = pentet, sex = sextet, sep
Acknowledgements
= septet, oct = octet, m = multiplet, br = broad), coupling con-
stant in Hertz (Hz), and integration. Chemical shifts of 13C
Financial support provided by the NIH (GM 86485) for our
NMR spectra are reported in ppm from the central peak of
CDCl3 (77.23 ppm) on the δ scale. High resolution mass ana-
lyses were obtained using an APE Sciex QStar Pulsar quadru-
pole/TOF instrument (API) for ESI, or a GCT Premier TOF MS
(Waters Corp) for FI.
programs in green chemistry is warmly acknowledged with
thanks.
Notes and references
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General procedure for Zn-mediated reductions of alkyl halides
To a 5 mL round bottom flask or 5 mL microwave vial
equipped with a stir bar, and fitted with a rubber septum
under argon atmosphere was sequentially charged with Zn
(4 equiv.). Under a positive flow of argon was added via
syringe the 2 wt% TPGS-750-M/H2O solution (0.5 mL, 0.5 M).
While stirring vigorously, TMEDA (2 equiv.) was added via
syringe followed by the alkyl halide (0.25 mmol). The mixture
was vigorously stirred at rt until completion (monitored by
TLC and/or GC-MS) was determined. The mixture was diluted
with EtOAc and filtered through a pad of silica gel. The solvent
was removed via rotary evaporation. The crude was purified
by column chromatography (eluent: EtOAc–hexanes or Et2O–
hexanes) as necessary.
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General procedure for E Factor study
To a 5 mL microwave vial equipped with a stir bar, fitted with
a rubber septum and cooled under an argon atmosphere was
charged with Zn (4 equiv.). Under a positive flow of argon, was
added via syringe the 2 wt% TPGS-750-M/H2O solution
(1.0 mL, 1.0 M). While stirring vigorously, TMEDA (2 equiv.)
was added via syringe followed by but-3-yn-1-yl-2-chloro-2-
phenylacetate (1.0 mmol). The reaction was allowed to stir vig-
orously until complete. The product was extracted with EtOAc
using gentle stirring: (250 μL + 250 μL). To ease separation a
centrifuge can be used. The organic solvent was evaporated via
rotary evaporation. The crude product was purified by silica gel
column chromatography (eluent: gradient from 1 to 10%
EtOAc–hexanes) to provide the desired compound as a color-
less oil (170 mg, 90% yield).
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