Fluorinated and chlorinated benzaldehydes

Details Fluorinated and chlorinated benzaldehydes Fluorinated and chlorinated benzaldehydes

2000-09-01

2001-10-02

Richter, Johann (Department: 1621)

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

Organic compounds

Oxygen containing

C568S428000, C568S435000, C570S127000, C570S170000

Reexamination Certificate

active

06297405

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of aromatic aldehydes containing fluorine, and more particularly, to a formylation process for fluorinated aromatic derivatives through the reaction of fluorinated benzenes with carbon monoxide and aluminum chloride at a relatively low pressure, a low temperature, and in the presence of at most a catalytic amount of an acid (such as aqueous hydrochloric acid). The resultant fluorinated benzaldehydes are useful as precursors to the formation of a number of different compounds, such as dyestuffs, flavorings, fragrances, herbicidal compounds, nucleating agents, polymer additives, and the like. The inventive method provides a very cost effective and safe procedure for producing such fluorinated benzaldehydes in very high yields. The particular novel multi-substituted benzaldehydes are also encompassed within this invention.
BACKGROUND OF THE INVENTION
Aromatic aldehydes are prepared by two primary synthetic methods: a direct method which consists of attaching a CHO group onto an aromatic derivative, and an indirect method which consists of oxidizing a group which is already present on the aromatic derivative. There are several well known methods for electrophilically formylating aromatic compounds containing activating (electron-donating) substituents, but these fail completely or are impractical for aromatic compounds which contain electron withdrawing substituents such as fluorine. To overcome this dilemma, new synthetic processes are continually being developed.
A direct formylation method is disclosed within U.S. Pat. No. 4,588,844 to Kysela et al., which describes a reaction between an aromatic compound and urotropine (hexamethylenetetramine, HMT) in a hydrofluoric acid medium. Yields obtained for compounds such as fluorobenzene were rather low (about 30%) and are not suitable for industrial utilization.
Another direct formylation method is disclosed within by U.S. Pat. No. 5,068,450 to Crochemore et al., which discloses a process consisting of reacting methyl formate with an aromatic derivative in liquid hydrofluoric acid in the presence of boron trifluoride. Yields of fluorobenzaldehyde obtained by incorporating fluorobenzene in this process are high (about 85%) and reportedly give a single isomer, 4-fluorobenzaldehyde.
U.S. Pat. No. 5,138,099 to Lang also discloses a direct formylation procedure in which a fluorinated aromatic derivative (fluorobenzene, 2-fluorotoluene) is reacted with dichloromethyl methyl ether in methylene chloride in the presence of ferric chloride. Isomeric impurities are then selectively removed by halogenation with bromine. Although high isomeric purities are claimed, the use of toxic intermediates such as dichloromethyl methyl ether and an expensive halogenating agent such as bromine make this process unsuitable for industrial utilization.
Other methods for preparing fluorinated benzaldehydes are known which use halogen-exhange (HALEX) chemistry (Journal of Fluorine Chemistry 46, 529-537 (1990). This method involves the reaction of chlorinated benzaldehydes with a metal halide, usually potassium fluoride, in a polar solvent to give a fluorinated benzaldehyde. Since only halogens in “activated” positions (those ortho and para to a formyl group) undergo halogen-exchange, the scope of this method is somewhat limited.
Aromatic formylation has traditionally been performed, since its development in the late 1800s, by a Gattermann-Koch procedure which comprises the reaction of the aromatic derivative with carbon monoxide, hydrogen chloride, and an appropriate catalyst (usually aluminum chloride). This standard reaction required the combination of equivalent amounts of aluminum chloride, carbon monoxide, and gaseous hydrogen chloride reacted in the presence of a substituted benzene. The temperature was controlled from 25 to 50° C., and the pressure was kept at 1,000 psig. Such a reaction yielded about 70% of the desired substituted benzaldehyde; however, the utilization of gaseous HCl and the need for high reaction pressures are highly undesireable from a safety standpoint. Modifications of the Gattermann-Koch reaction have been developed for specific monoalkyl-substituted benzaldehydes, such as in U.S. Pat. No. 4,622,429 to Blank et al. and di- and trialkyl-subsituted benzaldehydes in U.S. Pat. No. 4,195,040 to Renner.
While Gattermann-Koch chemistry works extremely well to prepare benzaldehyde, monoalkyl-, and polyalkyl-benzaldehydes, its use in preparing fluorinated benzaldehydes has gone virtually unexplored. Only one example is known whereby a fluorinated benzaldehyde was obtained from Gattermann-like conditions (Journal of Practical Chemistry 135, 101-127 (1932); C.A. 27, 713). In this example 3-fluoro-4-ethoxybenzaldehyde was obtained in 40% yield from the reaction of 1-fluoro-2-ethoxybenzene with zinc cyanide, hydrogen chloride, and aluminum chloride.
Even with these methods, there still remains a need in the art for methods of synthesizing fluorinated benzaldehydes in high isomeric purity and in a commercially viable manner that does not use highly toxic, corrosive, and costly reagents.
OBJECTS OF THE INVENTION
Therefore, an object of the invention is to provide a process for producing high yields of fluorinated and chlorinated benzaldehydes. A further object of the invention is to provide a highly cost-effective manner of producing such benzaldehydes which heretofore could not be produced in high yields without incurring potential problems from a safety perspective, particularly in a large scale procedure. Additionally, it is an object of this invention to provide a method of producing specific fluorinated and chlorinated benzaldehydes which requires, if at all, only a very low amount of HCl (aqueous, dry, or gaseous) in order to effectuate the necessary formylation procedure.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, this invention encompasses a method of producing a benzaldehyde of formula (I)
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are selected from hydrogen, lower alkyl groups containing 1-4 carbon atoms, cycloalkyl or cycloalkylene ring systems, fluorine, chlorine; with the proviso that one and only one of R
1
, R
2
, R
3
, R
4
, and R
5
is fluorine or chlorine and wherein at least one of the remaining groups is a moiety other than H; which comprises contacting a substituted benzene of formula (II)
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are selected from hydrogen, lower alkyl groups containing 1-4 carbon atoms, cycloalkyl or cycloalkylene ring systems, fluorine, chlorine; with the proviso that one and only one of R
1
, R
2
, R
3
, R
4
, and R
5
is fluorine or chlorine, and at least one of the other groups is a moiety other than H, in a carbon monoxide atmosphere having a pressure from about 200-800 psig, all in the presence of a metal halide, an acid selected from the group consisting of HCl, HBr, HF, HI, and mixtures thereof; wherein the acid is present in a catalytic amount of from about 0.005 to about 0.01 moles per moles of the metal halide; and wherein the reaction temperature is from about 30° to 100° C.
Any mono-halogenated benzene may be introduced within the inventive method. Specific compounds include fluorobenzene, 2-fluorotoluene, 2-chlorotoluene, 2-fluoro-m-xylene, 3-fluoro-o-xylene, 2-chloro-m-xylene, 3-chloro-o-xylene, 1-fluoro-2,3,6-trimethylbenzene and 1-chloro-2,3,6-trimethylbenzene.
The metal halide is preferably aluminum chloride, although other such halides may be utilized, such as aluminum bromide, iron (III) chloride, copper (II) chloride, zinc chloride, zirconium chloride, zirconium bromide, and the like. Also partially hydrated metal halides may be utilized as these produce acid (such as hydrochloric acid) upon dissociation within the reaction vessel, thereby providing the necessary aqueous acid component (for instance AlCl
3
XH
2
O wherein X is at most 1, preferably lower than 0.5, and most preferably between 0.01 and 0.1). This dissociation actually produces the requisite small, catalytic amount of aqueous hydroch

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