Use of compressed CO2 in chemical reactions

Details Use of compressed CO2 in chemical reactions Use of compressed CO2 in chemical reactions

2000-07-28

2002-10-01

Barts, Samuel (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S051000

Reexamination Certificate

active

06458985

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the use of compressed CO
2
in chemical reactions. More particularly, it relates to homogeneous catalysis in compressed CO
2
, e.g. metal-catalysed reactions, and also to the synthesis of cross-linked polymers in CO
2
.
BACKGROUND OF THE INVENTION
Metal-catalysed processes are extremely common in the formation of organic molecules, in particular pharmaceuticals, agrochemicals, flavours, fragrances and other consumer products. The use of a coordinating ligand, in such transformations, allows control of such variables as reaction rates, asymmetric induction, solubility, functional group specificity, product distribution and the yield of the process.
Metal-catalysed processes are typically conducted in conventional organic solvents (VOCs—volatile organic compounds). However, these materials have several drawbacks associated with their use. VOCs can be expensive, toxic (benzene, chlorofluorocarbons, acetonitrile), flammable (diethyl ether), restricted in availability (CFCs), difficult to process (solvent residues) and have associated disposavrecycling problems.
Compressed carbon dioxide is an attractive solvent for the preparation of organic molecules because it is inexpensive, non-toxic, and non-flammable. Unlike conventional liquid solvents, compressed CO
2
is highly compressible and the density (and therefore solvent properties) can be tuned over a wide range by varying the pressure. Moreover, compressed CO
2
reverts to the gaseous state upon depressurisation, greatly simplifying the separation of solvent from solute(s) and thereby reducing solvent residues in the products.
The metal-catalysed formation of organic molecules, in compressed CO
2
, has been very limited: hydrogenation [Burk et al, J. Am. Chem. Soc. (1995) 117, 8277; Jessop et al,
Nature
(1994) 368, 231], hydroformylation [Kainz et al,
Angew. Chem. Int. Ed. Engl.
(1997) 36, 1628] and others [Furstner et al,
Angew. Chem. Int. Ed. Engl. (
1997) 36, 2466] have been reported.
WO-A-9601851 discloses polymerisation processes, including olefin metathesis in CO
2
. A fluorinated dispersing agent may be used.
Cross-linked polymer resins are useful in a wide range of applications, including solid-phase synthesis, combinatorial chemistry, polymer-supported reagents, molecular imprinting, size-exclusion chomatography, ion-exchange resins, medical diagnostics, and the controlled release of drugs. In all of these various applications, it is often desirable to produce the cross-linked resins in the form of uniform microspheres. This is usually achieved by heterogeneous methods such as suspension, dispersion, or emulsion polymerisation [Arshady, Colloid Polym. Sci., (1992) 270, 717]. Typically, amphiphilic surfactants or stabilisers are used to prevent particle coalescence in these processes; however, residual surfactant on the particle surfaces may sometimes impair the performance properties of the resulting polymers. The formation of uniform cross-linked polymer microspheres has been achieved in the absence of surfactants; however, the solvents employed are often toxic (e.g., acetonitrile) [Li et al, J. Polym. Sci., Part A, Polym. Chem., 1993, 31, 3257] and/or expensive (e.g. perfluorocarbons) [Zhu, Macromolecules (1996) 29, 2813].
Supercritical carbon dioxide (scCO
2
) is an attractive solvent for polymer chemistry because it is inexpensive, non-toxic, and non-flammable [Canelas et al, Adv. Polym. Sci. (1997) 133, 103]. Unlike conventional liquid solvents, scCO
2
is highly compressible and the density (and therefore solvent properties) can be tuned over a wide range by varying pressure. Moreover, scCO
2
reverts to the gaseous state upon depressurisation, greatly simplifying the separation of solvent from solute(s). scCO
2
has been used as a solvent medium for homogeneous polymerisations [DeSimone et al, Science (1992) 257, 945; and PCT/US93/01626] and heterogeneous precipitation polymerisations [Romack et al, Macromolecules (1995) 28, 912]. In many cases, the precipitation polymerisation of polymers which are insoluble in scCO
2
occurs, to give low polymer yields and undefined, agglomerated polymer morphologies [Canelas et al, supra].
Polymeric surfactants or stabilisers have been developed which allow the synthesis of CO
2
-insoluble polymers in scCO
2
in high yields by dispersion polymerisation [DeSimone et al, Science (1994) 265, 356; Canelas et al, Macromolecules (1997) 30, 5673; U.S. Pat. No. 5,679,737]. By using the appropriate surfactants or stabilisers, it was possible to generate these polymers as uniform microspheres. All of these examples relate to the polymerisation in scCO
2
of monomers containing a single polymerisable functional group (e.g. styrene, methyl methacrylate, acrylic acid) and not bi- or multi-functional monomers of the type known to promote cross-linking in polymerisations (e.g. divinylbenzene (DVB), trimethylol propane trimethacrylate (TRM), ethylene glycol dimethacrylate (EGDMA)).
U.S. Pat. No. 4,748,220 discloses that cross-linked polymer particles were formed in liquid or supercritical CO
2
. The polymers were formed as pulverulent powders with primary particles in the size range 0.5-3 &mgr;m; however, the particles were not formed as regular microspheres. The use of scCO
2
to form cross-linked nanoporous polymer monoliths [U.S. Pat. No. 5,629,353] and microcellular cross-linked foams [U.S. Pat. Nos. 5,128,382; 4,748,220; 5,066,684] has also been described.
SUMMARY OF THE INVENTION
A first aspect of the present invention is based on the surprising observation that the incorporation of perfluorinated chains dramatically increases the solubility of ligand-metal complexes in compressed CO
2
, and enables metal-catalysed reactions to take place in a non-polar medium without chemical participation of the carbon dioxide. This improved solubility allows the ligand metal complexes to act as homogeneous catalysts. In particular, fluorinated phosphines are useful in palladium-catalysed processes. An application of particular value is where a reactant is immobilised on a material that swells in the presence of CO
2
.
A second aspect of the present invention is based on the surprising discovery that a range of cross-linked polymers can be formed using compressed CO
2
as the polymerisation medium, and that the polymers can be isolated in high yields directly from the reaction vessel as dry, free-flowing powders, in the form of discrete, uniform microspheres. This may be done, depending on the reactants and conditions, with or without the use of added surfactants. The invention thus provides for the synthesis of a range of cross-linked copolymers in CO
2
for a variety of potential applications, including molecular imprinting, solid-phase synthesis, combinatorial chemistry, polymer supported reagents, size-exclusion chomatography, and medical diagnostics.
The polymerisation route is simple, polymer yields are high, the solvent can be easily separated from the products, and the procedure allows the formation of uniform polymer microspheres with diameters in the range 1-5 &mgr;m by suspension or precipitation polymerisation, from styrenic monomers, without the use of any surfactants or stabilisers. When surfactants are used, smaller particles with controlled sizes of less than 0.5 &mgr;m diameter can be formed by emulsion polymerisation.
DESCRIPTION OF THE INVENTION
The first aspect of this invention typically uses fluorinated phosphorus-derived ligands of the formula
wherein X is selected from O, S and Se or may simply be an unshared pair of electrons. Preferably, X is O or S. Most preferably, is X is an unshared electron pair.
R
1
, R
2
and R
3
may each be any non-interfering group. Examples are alkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, thioalkyl, thioaryl, thioheteroaryl, aminoalkyl (primary, secondary, tertiary), aminoaryl, imino.
Preferably, R
1
or R
2
carries a perfluorinated carbon chain

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