Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
1999-12-03
2002-03-26
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S309000, C568S322000
Reexamination Certificate
active
06362375
ABSTRACT:
BACKGROUND OF THE INVENTION
Aromatic or aryl ketones are commonly used both as chemical intermediates and for producing many useful products. Methods to produce these compounds generally involve condensation of a carboxylic acid derivative with an active aromatic compound. The Friedel-Crafts acylation reaction, which introduces an acyl group into an aromatic ring to produce an aryl ketone, is considered the most important method for the formation of aryl ketones and is widely used commercially. In its most common form, the reaction occurs between an acyl halide, generally an acyl chloride, and an aromatic substrate and is catalyzed by aluminum trichloride. The mechanism of the reaction is represented by the following:
(March, J., “
Advanced Organic Chemistry
”, Third Edition, John Wiley & Sons, New York, 1985, 565-566).
Despite its widespread acceptance, this common method has a number of serious disadvantages, including the generation of significant amounts of toxic byproducts which must be disposed of as hazardous waste materials (Desmurs, J. R., et al., 1997
, Tetrahedron Lett
38:8871-8873). The amount and toxicity of the waste materials produced are a result of the chemical composition of the acyl chloride substrate and the aluminum chloride catalyst, the requirement for a stoichiometric amount of catalyst and the necessity of using a chlorinated hydrocarbon solvent, carbon disulfide or nitrobenzene (Smyth, T. R. et al., 1997
, Org Proc Res Dev
264). Moreover, the spent catalyst is not readily recoverable for reuse (Kawada, A. et al., 1993
, J Chem Soc, Chem Commun
1157-1158).
In recent years, much chemical and environmental research has been directed to improving the Friedel-Crafts acylation reaction. For example, attempts have been made to utilize substrates other than acyl halides for Friedel-Crafts acylation reactions. The majority of those methods utilize the readily reactive acyl anhydrides, but it has been recognized that these starting materials require catalyst in even greater amounts than do acyl halides. The additional catalyst is required due to the necessity for converting the acyl compound to the acyl cation (March, J., “
Advanced Organic Chemistry
”, Third Edition, John Wiley & Sons, New York, 1985, 565-566, 565). Moreover, such reactions only utilize a single acyl group, wasting the second acyl group.
A few studies have examined the direct use of carboxylic acid substrates. Unfortunately, these methods generally require the use of very strong or protic acids, such as hydrogen fluoride, sulfuric acid or polyphosphoric acid, as the catalyst (Lindley, D., et al., 1990, U.S. Pat. No. 4,894,482; Curtis, T. A. et al., U.S. Pat. No. 4,990,681; Sumner Jr., 1991,U.S. Pat. No. 5,041,616). Thus, the methods not only produce very toxic byproducts, they must be conducted in a highly corrosion-resistant environment.
The use of alternative catalysts has also been considered. For example, metal triflate salts have been used for organic synthesis reactions in general (Labrouillerer, M. et al., 1999
, Tetrahedron Lett
40:285-286), and Friedel-Crafts acylations in particular (Kawada, A. et al., 1993
, J Chem Soc, Chem Commun
1157-1158
; J Chem Soc
; Kawada, A. et al., 1994
,Synlett
7:545-546;Desmurs, J. R., et al., 1997
, Tetrahedron Lett
38:8871-8873). These studies utilized either acyl halides or anhydrides as substrates; therefore, the deficiencies associated with the use of those starting materials must be considered when evaluating these methods.
Thus, there exists a need for a more efficient and cost-effective method for producing aryl ketones that minimizes the generation of toxic byproducts.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the discovery of an efficient, cost-effective method useful for the production of aryl ketones that minimizes the generation of toxic byproducts. The method utilizes a carboxylic acid substrate which eliminates both the necessity for forming the acyl chloride starting material, and the reaction step in which the acid chloride intermediate is formed in the common Friedel-Crafts acylation reaction. The method also utilizes a metal triflate salt catalyst which can be recovered and reused after the reaction is complete. In addition, water, the major byproduct formed by the reaction, is collected and removed during processing.
In one embodiment, a method of preparing an aryl ketone represented by the following structural formula:
comprising heating an aromatic compound represented by the following structural formula:
with a carboxylic acid in the presence of (1) a volatile organic compound which forms an azeotrope with water, and (2) a catalytic amount of a metal triflate salt, wherein the water of reaction is removed from the reaction mixture, and wherein:
R
1
is the residue of the carboxylic acid;
R
2
is an a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy or halogen group;
R
3
is a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy or halogen group or any combination thereof; or
R
2
and R
3
collectively are a divalent chain of atoms forming a fused ring with the benzene ring to which each is attached.
In a preferred embodiment, the method is carried out at a temperature of less than about 85, 110, 132 or 140° C.
In a preferred embodiment, the volatile organic compound is an aliphatic or aromatic hydrocarbon. In a preferred embodiment, the volatile organic compound is an aryl halide. In particularly preferred embodiments, the volatile organic compound is toluene.
In a preferred embodiment, the metal triflate catalyst is a rare metal triflate catalyst. In a particularly preferred embodiment, the metal triflate catalyst is a rare earth metal triflate catalyst.
In another embodiment, an improved Friedel-Crafts acylation reaction is provided comprising the steps of generating an acylium ion through the acceptance of an electron pair from a carboxylic acid by a metal triflate catalyst, followed by loss of water in an organic solvent which forms an azeotrope with water; reacting the acylium ion with an aromatic substrate; and removing the water of reaction from the reaction mixture, thereby forming an aryl ketone.
In a preferred embodiment, the reaction is carried out at a temperature of less than about 85, 110, 132 or 140° C.
In a preferred embodiment, the volatile organic solvent is an aliphatic or aromatic hydrocarbon. In a preferred embodiment, the volatile organic compound is an aryl halide. In a particularly preferred embodiment, the volatile organic solvent is toluene.
In a preferred embodiment, the metal triflate catalyst is a rare metal triflate catalyst. In a particularly preferred embodiment, the metal triflate catalyst is a rare earth metal triflate catalyst.
In another embodiment, a method of preparing an aryl ketone represented by the following structural formula:
comprising heating an aromatic compound represented by the following structural formula at a temperature less than about 140° C.
with a carboxylic acid in the presence of (1) toluene, and (2) a catalytic amount of a rare earth metal triflate, wherein the water of reaction is removed from the reaction mixture, and wherein:
R
1
is the residue of the carboxylic acid;
R
2
is a hydrogen, hydroxy, alkyl alkoxy, aryl, aryloxy or halogen group;
R
3
is a hydrogen, hydroxy, alkyl, alkoxy, aryl, aryloxy, halogen group or any combination thereof; or
R
2
and R
3
collectively are a divalent chain of atoms forming a fused ring with the benzene ring to which each is attached.
DETAILED DESCRIPTION OF THE INVENTION
A description of preferred embodiments of the invention follows. It will be understood that the particular embodiments are shown by way of illustration and not as limitations. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention. All parts and percentages are by weight unless otherwise specified.
A variety of metal triflates can be used as catalysts in the methods of the invention. The language “metal triflate” is intended to include a compound
College of the Holy Cross
Hamilton Brook Smith & Reynolds P.C.
Padmanabhan Sreeni
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