Stereoselective bromination reactions using tridecylmethylphosphonium tribromide in a "stacked" reactor

Article abstract of DOI:10.1021/ol801327n

(Chemical Equation Presented) A new reagent, tridecylmethylphosphonium tribromide, and new procedures for bromination reactions of unsaturated substrates (including one that allows several substrates to be reacted in sequence) are described. The procedures exploit the diffusion of components and the densities and immiscibilities of layers, including a fluorous "spacer" layer, within a reaction vessel. The stereoselectivities achieved in the reactions are superior in some cases to those found with other brominating reagents.

Full text of DOI:10.1021/ol801327n

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4155-4158
Stereoselective Bromination Reactions
Using Tridecylmethylphosphonium
Tribromide in a “Stacked” Reactor
Kefeng Ma,† Shaw Li,‡ and Richard G. Weiss*,†
Department of Chemistry, Georgetown UniVersity, Washington, D.C. 20057-1227
weissr@georgetown.edu
Received June 11, 2008
ABSTRACT
A new reagent, tridecylmethylphosphonium tribromide, and new procedures for bromination reactions of unsaturated substrates (including
one that allows several substrates to be reacted in sequence) are described. The procedures exploit the diffusion of components and the
densities and immiscibilities of layers, including a fluorous “spacer” layer, within a reaction vessel. The stereoselectivities achieved in the
reactions are superior in some cases to those found with other brominating reagents.
Bromination reactions of unsaturated molecules involving
additions or electrophilic substitutions are common in organic
synthesis. Typically, they are performed in batch processes
by dissolving the substrate and the brominating reagent in a
common solvent. However, the most common of these
reagents, bromine, is difficult to manipulate due to its
toxicity, corrosiveness, and high vapor pressure. Although
several other brominating reagents1-3 have been introduced
to minimize these problems, new reagents are needed for
specific applications, especially if they reduce the environ-
mental impact of the reactions.
Here, we describe how a new ionic liquid, tridecylmeth-
ylphosphonium tribromide (1P10Br3), can be used in bro-
mination processes, including one in which several reactions
are conducted sequentially, without classical workup pro-
† Georgetown University.
‡ Undergraduate research participant from College of Chemical and Life
Sciences, University of Maryland, College Park, MD 20742.
(1) (a) De Meijere, A.; Diederich, F., Eds. Metal-catalyzed Cross-
coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Rajasingh,
P.; Cohen, R.; Shirman, E.; Shimon, L. J. W.; Rybtchinski, B. J. Org. Chem.
2007, 72, 5973–5979. (c) Bhatt, S.; Nayak, S. K. Syn. Commun. 2007, 37,
1381–1388. (d) Suresh, P.; Annalakshmi, S.; Pitchumani, K. Tetrahedron
2007, 63, 4959–4967. (e) Adimurthy, S.; Ramachandraiah, G.; Bedekar,
A. V.; Ghosh, S.; Ranu, B. C.; Ghosh, P. K. Green Chem. 2006, 8, 916–
922. (f) Lakouraj, M. M.; Tajbakhsh, M.; Mokhtary, M. J. Chem. Educ.
2005, 481–483. (g) Okada, Y.; Yokozawa, M.; Akiba, M.; Oishi, K.;
O-kawa, K.; Akeboshi, T.; Kawamura, Y.; Inokuma, S.; Nakamura, Y.;
Nishimura, J Org. Biomol. Chem. 2003, 1, 2506–2511. (h) Das, J. P.; Say,
S. J. Org. Chem. 2002, 67, 7861–7864. (i) Nair, V.; Panicker, S. B.;
Augustine, T.; George, T. G.; Thomas, S.; Vairamani, M. Tetrahedron 2001,
57, 7417–7422. (j) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.
Tetrahedron 1999, 55, 11127–11142. (k) Hazra, B. G.; Chordiam, M. D.;
Bahule, B. B.; Pore, V. S.; Basum, S. J. Chem. Soc., Perkin Trans. 1 1994,
1667–1669. (l) Ho, T. L.; Gupta, B. G. B.; Olah, G. A. Synthesis 1977,
676–677. (m) Sekiyam, M.; Ito, K.; Suzuki, K. Tetrahedron 1975, 31, 231–
233.
(2) (a) Bose, G.; Mondal, E.; Khan, A. T.; Bordoloi, M. J. Tetrahedron
Lett. 2001, 42, 8907–8909. (b) Bellucci, G.; Chiappe, C.; Lo Moro, G. J.
Org. Chem. 1997, 62, 3176–3182. (c) Berthelot, J.; Benammar, Y.; Lange,
C. Tetrahedron Lett. 1991, 32, 4135–4136. (d) Berthelot, J.; Fournier, M.
J. Chem. Educ. 1986, 63, 1011
.
(3) (a) Salazar, J.; Dorta, R. Synlett 2004, 7, 1318–1320. (b) Tanaka,
K.; Shiraishi, R.; Toda, F. J. Chem. Soc., Perkin Trans. 1 1999, 3069–
3070
.
10.1021/ol801327n CCC: $40.75
Published on Web 08/29/2008
2008 American Chemical Society

cedures. 1P10Br3 is made by reaction of tridecylmethylphos-
phonium bromide (1P10Br)4 with molecular bromine (eq
1), and it is replenished in situ during the brominations
(Scheme S1 of Supporting Information).
detected by UV-vis spectroscopy in a neat upper hexadecane
layer that was in contact with 1P10Br3 for two weeks,
reaction with substrates is proposed to occur only at the
1P10Br3-hexadecane layer interface. Thus, the careful
control of both temperature and addition of molecular
bromine, which are needed to avoid undesirable side reac-
tions in solution-phase brominations with Br2,10 is not
necessary here. Table 1 summarizes the yields and distribu-
tions of products with 1P10Br3 as the brominating reagent
using different protocols.
5
Batch Reactions (Two-Layer Systems). Typically, a
vessel was loaded with 1P10Br3 and an upper layer of
hexadecane with dissolved substrate, capped to avoid evapo-
ration or introduction of moisture, and left undisturbed until
workup. To increase somewhat the rates of these bromina-
tions, a slight molar excess of 1P10Br3 was added. When
the brominated products were solids, they were easily isolated
by gravity filtration followed by washing with hexane in
which 1P10Br is soluble. The 1P10Br is easily recovered
by evaporation of the hexane, and 1P10Br3 can be regener-
ated by addition of more bromine. In those cases where the
products are soluble in hexadecane, the upper layer can be
removed with a pipet, followed by one of a variety of
separation techniques that depends on the relative boiling
points or column elution characteristics of the components.
A detailed description of the physical isolation of a liquid
and a solid bromination product is provided in the Supporting
Information file.
The bromination of cis-stilbene in hexadecane by 1P10Br3
was almost exclusively syn (producing meso-1,2-dibromo-
1,2-diphenylethane) and in a reasonable chemical yield (entry
3 in Table 1). No mesohd,l isomerization of product was
observed under these reaction conditions. Reaction with
1P10Br3 dissolved in 1,2-dichloroethane or with bromine
in hexadecane (entry 3) was almost exclusively anti, as
expected,11 providing the d,l stereoisomer. The Br3- reagents
with ammonium counterions also yielded exclusively or
predominantly the isomer from anti addition either in solvent-
free3a or solution reactions.2b,6 The observation of syn
bromination at a high cis-stilbene concentration (ca. 0.3 M)
in hexadecane appears to be unprecedented. In 1,2-dichlo-
roethane solutions, the maximum syn/anti ratio, 9/1, has been
reported at the lowest cis-stilbene (∼10-5 M) and the highest
Br2 (∼10-3 M) concentrations employed.12 We conjecture
that the syn addition with 1P10Br3 is related to the manner
in which stilbene molecules sit on the surface of the 1P10Br3
layer. However, no syn addition to trans-stilbene was
observed with 1P10Br3, although it does occur in solution!12
More experimentation will be required to understand the
mechanisms responsible for these results.
-
The tribromide anion, Br3 , is very stable when neat or
dissolved in aprotic solvents6 and is a safer and more easily
handled reagent because it lacks the volatility of molecular
bromine. Its quaternary ammonium salts can effect bromi-
nation reactions in solutions or as solids,2,3 and they have
been used to catalyze several acetalization and pyranylation
reactions.7 The results presented here demonstrate how the
larger size of P+ than N+, its lower binding energy with
anions,8 and the broadened liquid phase range of 1P10Br3
may be exploited to brominate a wide variety of substrates.
4
Characterization of 1P10Br3. Both the larger size and
more delocalized electrons of the Br3 anion contribute to
-
the drastically lower melting temperature of 1P10Br3 (-19.8
to -26.3 °C upon cooling by optical microscopy and DSC;
Figure S1-A of Supporting Information) than of 1P10Br
(98.8-100.7 °C4g).
The X-ray diffractogram of 1P10Br3 in the liquid phase
at room temperature contains a weak, low-angle peak
corresponding to d ) 18.2 Å from residual molecular packing
of tridecylmethylphosphonium ions4g (Figure S1-B of Sup-
porting Information). The broad peak centered near 22°
(corresponding to a Bragg distance of ∼4.0 Å) is attributed
to interchain interactions from London dispersion forces.9
1P10Br3 as a Brominating Reagent. 1P10Br3 is insoluble
in long alkanes. Its red color was slowly lost as bromination
occurred when it was added to a solution of hexadecane
containing an unsaturated substrate. Because no bromine was
(4) (a) Abdallah, D. J.; Bachman, R. E.; Perlstein, J.; Weiss, R. G. J.
Phys. Chem. B 1999, 103, 9269–9278. (b) Abdallah, D. J.; Robertson, A.;
Hsu, H.-F; Weiss, R. G. J. Am. Chem. Soc. 2000, 122, 3053–3062. (c)
Abdallah, D. J.; Weiss, R. G. Chem. Mater. 2000, 12, 406–413. (d) Abdallah,
D. J.; Lu, L.; Cocker, M. T.; Bachman, R. E.; Weiss, R. G. Liq. Cryst.
2000, 27, 831–837. (e) Hui, C.; Kwait, D. C.; Go¨nen, Z. S.; Weslowski,
B. T.; Abdallah, D. J.; Weiss, R. G Chem. Mater. 2002, 14, 4063–4072. (f)
Abdallah, D. J.; Wauters, H. C.; Kwait, D. C.; Khetrapal, C. L.; Nagana
Gowda, G. A.; Robertson, A.; Weiss, R. G. Ionic Liquids IIIB: Fundamental,
Progress, Challenges and Opportunities (ACS Symposium Series 902);
Rogers, R. D., Seddon, K. R., Eds.; American Chemical Society: Wash-
ington, DC, 2005; Chap 21, pp 303-320. (g) Ma, K.; Somashekhar, B. S.;
Nagana Gowda, G. A.; Khetrapal, C. L; Weiss, R. G. Langmuir 2008, 24,
2746–2758.
(5) Slebocka-Tilk, H.; Ball, R. G.; Brown, R. S. J. Am. Chem. Soc. 1985,
107, 4504–4508.
Batch Reactions (Four-Layer System). A bromination
system employing four separate liquid layers was also
devised. Examples employing 1P10Br3 and 1P10Br as the
(6) Bianchini, R.; Chiappe, C. J. Org. Chem. 1992, 57, 6474–6478.
(7) (a) Naik, S.; Gopinath, R.; Goswami, M.; Patel, B. K. Org. Biomol.
Chem. 2004, 2, 1670–1677. (b) Gopinath, R.; Haque, S. J.; Patel, B. K J.
Org. Chem. 2002, 67, 5842–5845. (c) Naik, S.; Gopinath, R.; Patel, B. K.
Tetrahedron Lett. 2001, 42, 7679–7681. (d) Gopinath, R.; Patel, B. K. Org.
Lett. 2000, 2, 4177–4180.
(10) (a) Org. Synth. Coll.; 1941; Vol. 1, p 521. (b) Org. Synth. Coll.;
1943; Vol. 2, p 171. (c) Chiappe, C.; Capraro, D.; Conte, V.; Pieraccini, D.
Org. Lett. 2001, 3, 1061–1063.
(8) Swartz, W. E.; Ruff, J. K.; Hercules, D. M. J. Am. Chem. Soc. 1972,
94, 5227–5229.
(11) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, Part
B, 4th ed.; Kluwer: New York, 2000; pp 200-202.
(12) Bellucci, G.; Bianchini, R.; Chiappe, C.; Marioni, F. J. Org. Chem.
1990, 55, 4094–4098.
(9) (a) Martin, S. M.; Yonezawa, J.; Horner, M. J.; Macosko, C. W.;
Ward, M. D. Chem. Mater. 2004, 16, 3045–3055. (b) Felekis, T.; Tziveleka,
L.; Tsiourvas, D.; Paleos, C. M. Macromolecules 2005, 38, 1705–1710.
4156
Org. Lett., Vol. 10, No. 19, 2008

Table 1. Product Yields and Distributions of syn/anti Dibrominated Addition (or Other) Products for Reactions of Various Substrates at
Room Temperature Using Three Experimental Protocols (See Supporting Information file for product NMR spectra)
a Based on product stereochem for entries 1-8. b Average of two experiments. c From sequential bromination experiments; see below. d Plus 36%
9-bromophenanthrene.e Stirredthelast2days.f Plus32%9-bromophenanthrene.g 1.0equivofBr2.h trans-1,2-Dibromo-1,2-diphenylethene:1,1,2,2,-tetrabromo-1,2-
diphenylethane. i 4-Bromoanisole:2,4-dibromoanisole:2,4-dibromophenol (4 layer) or 4-bromoanisole:2,4-dibromoanisole:2-bromoanisole (Br2/hexadecane).
j 4-Bromoanisole:2,4-dibromoanisole.
initial reagent are shown in Figure 1.13 Both permit consumed
1P10Br3 (i.e., 1P10Br) to be regenerated in situ without the
unsaturated substrates coming into direct contact with
molecular bromine. Our design, based on solubilities and
densities, is an extension of the clever use of perfluorohexane
(d ) 1.67 g/mL) by Ryu, Curran, and co-workers14 and Jana
and Verkade15 as a moderating layer in “phase-vanishing”
bromination reactions. In our case, perfluorohexane separates
the bromine layer at the bottom (d ) 3.12 g/mL) from the
1P10Br3 ionic liquid layer (0.77 g/mL < d < 1.67 g/mL)
and hexadecane/substrate top layers (d ) 0.77 g/mL). The
rate of bromine transport can be controlled by the thicknesses
of the perfluorohexane and phosphonium salt layers or by
immersing the bromine and perfluorohexane layers in a cold
bath.16
Perfluorohexane, being heavier than 1P10Br3 or 1P10Br
but lighter than liquid bromine and immiscible in both, serves
as a membrane to regulate diffusion of bromine14 into the
1P10Br/1P10Br3 layer: 1P10Br3 that is lost during reaction
with substrate is replenished; the liquid nature of the
phosphonium phase is maintained; and the top layer,
containing hexadecane and a substrate, continues to be
exposed to an adequate amount of 1P10Br3. As will be
discussed later, this system is also amenable to conducting
sequential bromination reactions without dismantling it
between changes of substrates.
Tribromide anions can associate with one additional Br2
6
-
molecule to form Br5 . Such a species, 1P10Br5, may be
present here, and its presence is indicated by the red layer
in Figure 1B at the end of the reaction (in which an excess
of molecular bromine was added): the bromine layer has
disappeared completely; the perfluorohexane and hexadecane
layers are colorless; and even with the 100% product yield
found (entry 4 in Table 1), there remain 1.2 molecules of
Br2 per molecule of 1P10Br.17
(13) We have not observed large differences in the outcomes of reactions
conducted with the two salts. The syn/anti ratio for products from cis-stilbene
was 97/3 when 1P10Br was the initial salt in contact with the hexadecane
layer (as compared to 94/6 reported in Table 1 using 1P10Br3). However,
use of 1P10Br3 is recommended in general because, in some cases, bromine
that diffuses from below may react more slowly with the solid 1P10Br
than it diffuses through the phosphonium layer and reacts with molecules
in the upper hexadecane layer.
Product ratios are based on areas of diagnostic peaks in
1H NMR spectra of reaction mixtures (see the Supporting
Information file). The results indicate that the use of 1P10Br3
(14) (a) Ryu, I.; Matsubara, H.; Yasuda, S.; Nakamura, H.; Curran, D. P.
J. Am. Chem. Soc. 2002, 124, 12946–12947. (b) Rahman, M. T.; Kamata,
N.; Matsubara, H.; Ryu, I. Synlett 2005, 2664–2666.
(16) Maass, O.; McIntosh, D. Br2 freezes at -7.3 °C. J. Am. Chem.
Soc. 1912, 34, 1273–1290.
(15) Jana, N. K.; Verkade, J. G. Org. Lett. 2003, 5, 3787–3790.
Org. Lett., Vol. 10, No. 19, 2008
4157

Information file). After each bromination, the hexadecane
layer (containing the soluble products) was removed with a
pipet. More bromine was added through a sidearm with a
column of perfluorohexane when a new substrate in hexa-
decane was added above the phosphonium salt layer. Because
the bromination products from cis-stilbene are insoluble in
hexadecane, it was reacted last. Results from these and from
the two-phase batch system for the same substrates are very
similar (Table 1). At the end of the sequence, there was no
indication of degradation of the phosphonium salt; the
bromination system is a rechargeable “green” reactor.
In conclusion, we have used a new ionic liquid, 1P10Br3,
to brominate a variety of substrates using three reactor
conditions, including two that depend on the densities and
immiscibilities of four species. The reactions require mild
conditions and, in some cases, are more stereoselective than
other reagents. Sequential brominations of substrates within
one reactor have been demonstrated as well. Thus far, we
have not attempted to optimize the bromination conditions.
Clearly, it should be possible to increase the rates at which
the reactions occur in two-layer batch reactions by rapidly
stirring or sonicating the mixtures. The rates of conversions
of reactions in the four-layer systems can be modulated as
well using variables, such as temperature, interfacial surface
areas, layer thicknesses, and even stirring within single layers.
Other possible variables to be explored in future work include
alteration of the structure of the phosphonium cation,4
performing iodinations and chlorinations with phosphonium
triiodides19 and trichlorides,20 and substituting other liquids
that dissolve brominated products better than hexadecane.
Figure 1. Four-layer brominating systems consisting of (from top
to bottom): (A) trans-2-hexene (72 mg, 0.86 mmol) in 2.1 mL of
hexadecane, 1P10Br3 (335 mg, 0.47 mmol; 5 mm in layer
thickness), perfluorohexane (1.42 g; 11 mm layer thickness), and
bromine (163 mg, 1.02 mmol), and (C) cis-stilbene (135 mg, 0.75
mmol) in 3.2 mL of hexadecane, small solid pieces of 1P10Br (412
mg, 0.75 mmol; 5 mm in layer thickness), perfluorohexane (2.25
g; 13.5 mm layer thickness), and bromine (120 mg, 0.75 mmol).
The interior diameters of the round tube in A/B and C/D are 10.5
mm (87 mm2 surface area) and 11.5 mm (104 mm2 surface area),
respectively. Initial stages of the reaction in A and C show that
bromine has already begun to diffuse through the perfluorohexane
layer (red gradient). B and D show the loss of the bromine layer
with time and residual bromine in the phosphonium layer. Note
the crystals of 1,2-dibromo-1,2-diphenylethane atop the phospho-
nium salt layer in the expanded view of D.
has some distinct stereochemical advantages in some cases
but is not the method of choice in others due to lower yields
(entry 7) or longer periods needed to obtain high product
yields (entries 1, 4, and 5).
However, brominations using 1P10Br3 are the most
stereoselective of the methods examined for trans-stilbene
(entry 2) and acenaphthylene (entry 6) and the most
chemoselective for diphenylacetylene (entry 8). Interestingly,
bromination of anisole (entry 9) using the two-layer system
with 1P10Br3 resulted in exclusive para-substitution, albeit
in a low yield. Surprisingly, the total yield of bromination
products is improved significantly by employing the four-
layer system, but it was attended by formation of some 2,4-
dibromoanisole and 2,4-dibromophenol (from disubstitution
and ether cleavage).
Acknowledgments. We are grateful to the U.S. National
Science Foundation for financial support of this research and
to Dr. Al Robertson of Cytec Corporation for supplying the
precursor tri-decylphosphine.
Supporting Information Available: Instrumentation,
sample preparations, NMR spectra of brominated products
and procedures for their isolation, phase characterizations
of 1P10Br3 by differential scanning calorimetry and X-ray
diffractometry, and experimental procedures for different
bromination methods. This material is available free of
charge via the Internet at http://pubs.acs.org.
Sequential Brominations (Four-Layer System). In a
demonstration of principle, we have brominated trans-2-
hexene, cis-2-hexene, and cis-stilbene in sequence without
disassembling the reactor (Figure S218 and Supporting
OL801327N
(17) We have not compared as yet the regio- and stereoselectivities of
brominations using 1P10Br3 and 1P10Br5. The configurations of our
systems strongly suggest that 1P10Br3 is the dominant brominating agent
in the work reported here.
(19) (a) Ramette, R. W; Sandford, R. W., Jr J. Am. Chem. Soc. 1965,
87, 5001–5005. (b) Topol, L. E. Inorg. Chem. 1968, 7, 451–454. (c) Johnson,
A. E.; Myers, A. B. J. Phys. Chem. 1996, 100, 7778–7788. (d) Sato, H.;
Hirata, F.; Myers, A. B. J. Phys. Chem. A 1998, 102, 2065–2071.
(20) (a) Riedel, E. F.; Willett, R. D. J. Am. Chem. Soc. 1975, 97, 701–
704. (b) Babcock, L. M.; Thompson, D. L. J. Chem. Phys. 1983, 78, 2394–
2401.
(18) A slightly more sophisticated apparatus, which allows for the direct
addition of bromine to the bottom layer and direct removal of the hexadecane
layers, has been designed, and results from experiments in which it is used
will be reported in the future.
4158
Org. Lett., Vol. 10, No. 19, 2008