The Michaelis-Becker reaction in phosphonium and imidazolium ionic liquids

Article abstract of DOI:10.1080/10426500903329252

The Michaelis-Becker reaction was performed in imidazolium ionic liquids using sodium hydroxide as base or sodium dialkylphosphites with good yield and selectivities. The analogous reaction performed in phosphonium ionic liquids resulted in decomposition to phosphine oxides. Copyright

Full text of DOI:10.1080/10426500903329252

This article was downloaded by: [Pennsylvania State University]
On: 27 April 2013, At: 05:38
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
The Michaelis–Becker Reaction in
Phosphonium and Imidazolium Ionic
Liquids
a
a
a
Anh P. Vu , Erika A. Shaffer , Laura K. Byington Congiardo & D.
b
Andrew Knight
a
Department of Chemistry, Loyola University New Orleans, New
Orleans, Louisiana, USA
b
Chemistry Department, Florida Institute of Technology, Melbourne,
Florida, USA
Version of record first published: 25 Aug 2010.
To cite this article: Anh P. Vu , Erika A. Shaffer , Laura K. Byington Congiardo & D. Andrew Knight
(2010): The Michaelis–Becker Reaction in Phosphonium and Imidazolium Ionic Liquids, Phosphorus,
Sulfur, and Silicon and the Related Elements, 185:9, 1845-1849
To link to this article: http://dx.doi.org/10.1080/10426500903329252
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 185:1845–1849, 2010
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903329252
THE MICHAELIS–BECKER REACTION IN PHOSPHONIUM
AND IMIDAZOLIUM IONIC LIQUIDS
1
1
1
Anh P. Vu, Erika A. Shaffer, Laura K. Byington Congiardo,
2
and D. Andrew Knight
Department of Chemistry, Loyola University New Orleans, New Orleans,
1
Louisiana, USA
2
Chemistry Department, Florida Institute of Technology, Melbourne, Florida, USA
The Michaelis–Becker reaction was performed in imidazolium ionic liquids using sodium hy-
droxide as base or sodium dialkylphosphites with good yield and selectivities. The analogous
reaction performed in phosphonium ionic liquids resulted in decomposition to phosphine
oxides.
Keywords Imidazolium; ionic liquid; Michaelis–Becker; phosphonium
INTRODUCTION
The Michaelis–Becker reaction is arguably one of the most important carbon–
1
phosphorus bond forming reactions known. First reported in 1897, it has become the
reaction of choice for the synthesis of dialkyl esters of alkylphosphonic acids, along with
2
the related Michaelis–Arbuzov reaction. The Michaelis–Becker reaction involves the gen-
eration of a dialkylphosphite anion from an H-phosphonate using a strong anhydrous base,
e.g., an alkali metal or alkali metal hydride, and then subsequent quenching with an elec-
trophile to yield a phosphonate ester (Scheme 1). Due to the high concentrations of the
powerful phosphite nucleophile, unwanted side reactions resulting from mono-dealkylation
are often encountered. Replacing the highly reactive sodium metal or sodium hydride with
aqueous sodium hydroxide results in base-promoted hydrolysis of the product phosphonate
ester or H-phosphonate reactant, although these problematic side reactions can be mitigated
by the use of a phase-transfer catalyst.3
In addition to the problems described above, the Michaelis–Becker reaction requires
the use of anhydrous volatile organic compounds (VOCs) as solvents, with ether and THF
being the most commonly employed. In addition to ether volatility, explosive peroxide
Received 15 July 2009; accepted 11 September 2009.
We would like to acknowledge the National Science Foundation (NSF, Grant No. DUE-0535957) and the
Motorola Foundation for financial support. We would also like to thank R. Hartsock, W. D. Stegbauer, and R.
Barnum for early observations and preliminary data.
Address correspondence to D. Andrew Knight, Chemistry Department, Florida Institute of Technology, 150
West University Boulevard, Melbourne, FL 32901, USA. E-mail: aknight@fit.edu
1
845

1
846
A.P. VU ET AL.
O
P
O
P
RO
RO
RO
RO
1
2
. base/solvent
. R'X
H
R'
Scheme 1
formation and flammability are also of concern. The green chemistry community has em-
4
braced the use of ionic liquids (ILs) as solvents for a large number of organic reactions.
The advantages of replacing conventional organic solvents with ILs include (a) low volatil-
ity, (b) zero or low flammability/combustion, (c) high thermal capacity, and (d) ease of
separation of solvent from reaction mixture. We recently initiated a program to study the
formation of carbon–phosphorus bonds in ionic liquids, examples of which have not pre-
viously been reported. The discovery that sodium hydroxide can be employed as a base
5
in imidazolium derived ionic liquids, e.g., [bmim][BF4] (1a), and that Grignard reactions
6
can be performed in phosphonium ionic liquids such as CYPHOS IL101 (2) prompted us
to investigate the Michaelis–Becker reaction in this solvent medium. Herein we describe
(
a) the high-yielding and selective Michaelis–Becker reaction using NaOH as an anhy-
drous base in 1; (b) the reaction of sodium dialkylphosphites with alkyl halides in 2; and
c) exploratory 31P NMR studies on the nature of the phosphite anion in 2.
(
RESULTS AND DISCUSSION
Our initial exploratory experiments were focused on the alkylation of sodium di-
alkylphosphites generated from the corresponding secondary phosphites and sodium hy-
droxide in 1a. The reaction conditions used are similar to the classical Michaelis–Becker
reaction, although the yields are significantly improved due to the apparent suppression
of unwanted side reactions.3 For example, the reaction of dibutylphosphite with methyl
iodide and sodium hydroxide in 1a gave dibutyl methylphosphonate in 91% yield (Table
I). Similarly, reaction of dimethylphosphite with methyl iodide in the presence of sodium
,7
ꢁ
hydroxide gave dimethyl methylphosphonate in 80% yield (Scheme 1: R = R = Me).
31
In situ monitoring of these reactions in the ionic liquid solvent using P NMR showed
major peaks at 31.5 and 34.3 ppm, respectively, corresponding to the phosphonate products,
with very minor (<5%) peaks due to unwanted side-reactions. In a noteworthy comparison
Table I Yields and NMR data for Michaelis–Becker reactions in ionic liquids
ꢁ
3a (%)
31P NMRc
Entry
R
R
base
IL
1
2
3
4
5
6
7
Bu
Me
Bu
Bu
Bu
Et
Me
Me
Me
Me
Bz
NaOH
NaOH
la
la
la
lb
la
2
91
80
60
82
60
16
75
31.5
34.3
31.5
31.5
32.8
30.1
31.5
b
Na
b
Na
b
Na
c
Me
Me
Na
b
Bu
Na
2
a
Isolated yields.
b
Sodium organophosphonates were pre-prepared from Na metal prior to use.
P NMR spectra were recorded at 161.9 MHz in CDCl3 and referenced to external H3PO4.
c31

MICHAELIS–BECKER REACTION
1847
of selectivity, the reaction of dimethylphosphite with methyl iodide in the presence of a
phase transfer catalysts and using aqueous sodium hydroxide as a base, gave dimethyl
methylphosphonate in only 22% yield with a significant amount of H3PO3 as a byprod-
3
uct. Isolation of the phosphonate products from the ionic liquid reaction was achieved
via a three-phase extraction process (organic solvent/water/IL) and recovery/recycle of the
ionic liquid after washing with water to remove sodium salts followed by purification of
the phosphonate using column chromatography. The purity of isolated phosphonates was
1
31
confirmed with H and P NMR spectroscopy (see Table I) and compared to literature
9
values.
We also wanted to investigate the use of phosphonium ionic liquids such as 2 for
the Michaelis–Becker reaction, but under the conditions of our reactions, 2 could not be
utilized for the hydroxide promoted Michaelis–Becker reaction. Although Ramnial et al.
recently reported the use of phosphonium ionic liquids for reactions involving strong bases
6
such as Grignard reagents and N-heterocyclic carbenes, we discovered that 2 undergoes
base promoted decomposition in the presence of sodium hydroxide under the conditions
of the Michaelis–Becker reaction to give the corresponding trialkylphosphine oxides and
alkanes (Scheme 2). This is not too surprising as it has been known for some time that
tetralkylphosphonium hydroxides undergo base-promoted decomposition to give the cor-
10
responding phosphine oxides. The identity of the phosphine oxides were confirmed by
IR, mass spectrometry, H, 13C, and P NMR. Further studies are underway to determine
whether use of an ionic liquid solvent results in any kinetic acceleration or deceleration of
the hydrolysis reaction compared to other polar solvent systems.
1
31
P
O
+
hexane
+
OH
P
2
P
O
+
tetradecane
Scheme 2
Although phosphonium ionic liquids cannot be used with sodium hydroxide for the
Michaelis–Becker reaction, preformed sodium dialkylphosphites can be employed without
any noticeable decomposition of the ionic liquid. For example, the reaction of methyl iodide
and sodium dibutylphosphite, isolated as a crystalline solid from the reaction of sodium
metal with dibutylphosphite in n-butanol, gave dibutyl methylphosphonate in 75% yield

1
848
A.P. VU ET AL.
with no detectable phosphonium salt decomposition. Workup of the reaction was readily
achieved with an exhaustive three-phase extraction process. The addition of water and
hexane to the ionic liquid results in a three-phase mixture with the lower layer consisting
of water, the upper layer containing the organic product in hexane, and the middle layer
composed of the ionic liquid. Our attempts to prepare sodium dibutylphosphite directly in
the ionic liquids using Na metal or NaH were all unsuccessful. Similarly, the reaction of
sodium dibutylphosphite with methyl iodide in [bmim]BF4 and [bmim]PF6 gave dibutyl
methylphosphonate in 60% and 82% yields, respectively, and the extension to benzyl
chloride as an alkylating agent is summarized in Table I.
We were curious as to the nature of the phosphite anion in ionic liquid solution. Doak
11
and Freedman proposed five possible structures for the alkali salts of H-phosphonates.
The phosphonate form of the anion I and the phosphite form II are ambidentate ions, with
31
structure I being the most likely based on P NMR chemical shift values in coordinating
solvents such as THF and ether.12 In addition, there has been speculation as to whether the
sodium dialkylphosphites are truly ionic complexes, or whether they are covalent molec-
ular species such as III or IV (Figure 1).11 A dimeric structure was also suggested (not
shown). The presence of either the phosphite or phosphonate forms may be probed easily
31
using P NMR in ionic liquids because of the expected large difference in chemical shift
between the structural forms. Sodium dibutylphosphite was prepared in n-butanol, isolated
as a solvent-free solid and dissolved in 2. A 31P NMR spectrum was recorded immediately
and showed, in addition to the peak corresponding to 2, a broad resonance at 142.3 ppm,
O
RO
RO
RO
RO
Na+
Na+
P
P
O
I
II
O
P
RO
RO
Na
P
ONa
RO
RO
III
IV
-
-
R
Cl
X
+
N
Bu
N
Me
+
P
R'
R
R
1
1
a: X = BF -
2
4
b: X = PF -
R = C6H13, R' = C14H29
6
Figure 1 The structures of H-phoshonates (I–IV) and ionic liquids.

MICHAELIS–BECKER REACTION
1849
which is entirely consistent with the exclusive existence of either ionic or molecular phos-
phite forms II and IV within NMR detection limits. Sodium diethylphosphite recorded in
THF shows a single peak at 150.7 ppm,12 suggesting that alkali metal salts of secondary
dialkylphosphites have similar structures in both conventional polar organic solvents and
ionic liquids, and as such the higher selectivity for the Michaelis–Becker reaction in ionic
liquids remains to be explained. In summary, ionic liquids have been explored as alternative
solvents for the classical Michaelis–Becker reaction with the unexpected outcome that the
sodium hydroxide–promoted reaction proceeds relatively cleanly without dealkylation of
the phosphite or phosphonate product. We are currently investigating the mechanism of
this reaction and exploring additional C–P bond forming reactions in ionic liquids.
EXPERIMENTAL
Typical Procedure for Synthesis of Phosphonates
A 25 mL flask was charged with 1-butyl-3-methylimidazolium tetrafluoroborate
[bmim]BF4 (ca. 5 mL), pulverized NaOH (0.0512 g, 1.28 mmol), and a magnetic stir
bar. The flask was stirred and heated in an oil bath until the sodium hydroxide dissolved
and then removed from the oil bath. Then, dibutylphosphite (0.25 mL, 1.3 mmol) was
added to via syringe. The resulting mixture was stirred for 15 min, and iodomethane (0.08
mL, 1 mmol) was added to the flask in a single portion and the mixture was stirred for
12 h. The ionic liquid layer was extracted with diethyl ether (ca. 3 mL) and the ether layer
was removed under oil-pump vacuum. The resulting residue was chromatographed (silica
gel, 90:10 hexane:EtOAc) to give methyl dibutylphosphonate (0.189 g, 0.908 mmol, 91%
yield).
REFERENCES
1
2
3
4
. A. Michaelis and T. Becker, Chem Ber., 30, 1003 (1897).
. A. K. Battacharya and G. Thyagarajan, Chem. Rev., 81, 415 (1981).
. H. Fakhraian and A. Mirzaei, Phosphorus, Sulfur, and Silicon, 181, 511 (2006).
. D. J. Adams, P. J. Dyson, and S. J. Tavener, Chemistry in Alternative Reaction Media (Wiley,
Chichester, UK, 2004).
5
. For examples of the use of NaOH in ionic liquids see: (a) M. J. Earle, P. B. McCormac, and
K. R. Seddon, Green Chem., 2, 261 (2000); (b) R. J. C. Brown, P. J. Dyson, D. J. Ellis, and T.
Welton, Chem Commun., 1862 (2001); (c) D. W. Morrison, D. C. Forbes, and J. H. Davis, Jr.,
Tetrahedron Lett., 42, 6053 (2001).
6
7
. T. Ramnial, D. D. Ino, and J. A. C. Clyburne, Chem. Comm., 325 (2005).
. Our yields of phosphonates obtained when synthesized using the classical Michaelis–Becker
reaction were in the range 14–63%. See ref. [8].
8
. E. Muller, Ed., Methoden der organischen Chemie (Houben-Weyl), vol. 7 (George Thieme Verlag,
Stuggart, Germany, 1964).
9. A. K. Gupta, R. Kumar, D. K. Dubey, and M. P. Kaushik, J. Chem. Res., 328 (2007) and references
therein.
1
1
1
0. M. Zanger, C. A. Vander Werf, and W. E. McEwen, J. Am. Chem. Soc., 81, 3806 (1959).
1. G. O. Doak and L. D. Freedman, Chem. Rev., 61, 31 (1961).
2. W. Boenigk and G. H a¨ gele, Chem Ber., 117, 2287 (1984).