Halohydrin

Cyclization. Halohydrin. The elimination reaction of ethylene halohydrins on solid catalysts gives ethylene oxide or other products depending on the nature of the catalyst. Acetaldehyde was obtained using a solid acid catalyst supported on silica gel by halide-ion abstraction, ethylene from the less polar sites on metal surfaces by halogen-atom abstraction, and ethylene oxide from the basic sites by proton abstraction. Among some of the more unusual epoxides which have been formed by base treatment of the corresponding halohydrin are the polyfluorinated epoxides (89) and the C-labelled l-halogeno-2,3-epoxy[3- K )]propane (90) (X = Cl, Br, or I). 

Epoxides (91), (93), and (95) formed through the normal bromohydrin route are important intermediates in the ultimate synthesis of the polycyclic arene epoxides benz[a]anthracene 8,9-oxide (92), benz[a]pyrene 7,8-oxide (94), and benz[a]pyrene 9,10-oxide (96). Polycyclic arene oxides of the types (92), (94), (96), and (97) were found to bind to DNA and to stimulate DNA synthesis, mutagenesis, and carcinogenesis.  

The effect of solvent on alkaline hydrolysis and concomitant cyclization of bicyclo[2,2,l]heptane iodolactone (98) to the corresponding e/icfo-epoxide (99) has been investigated. Whereas epoxide (99) was the major product in dimethylformamide, alternative protic solvents yielded only the rearrangement product (100). The reaction of halohydrins with ethoxytributyltin is 

Kuroki, E. Huberman, H. Marquardt, J. K. Selkirk, C. Heidelberger, P. L. Grover, and P. Sims, Chem.-Biol. Interactions, 1972, 4, 389. 

Several examples of the formation of optically active epoxides by stereospecific cyclization routes have been reported. 2/5,3/5-Epoxypinane (106) was thus formed by monotosylation of (—)-pinane-2j5,3a-diol and cyclization of (105) with alcoholic potassium hydroxide. (— )-Propylene oxide has 

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On the other hand, the halohydrin (chloro and bromo) 908 is converted into a ketone via oxidative addition and //-elimination in boiling benzene with catalysis by Pd(OAc)2 and tri(o-tolyl)phosphine in the presence of K2C03[765,766],... 

When treated with bromine or chlorine in aqueous solution alkenes are con verted to vicinal halohydrins A haloni um ion IS an intermediate The halogen adds to the carbon that has the greater number of hydrogens Addition is anti... 

Reaction with base brings the alcohol function of the halohydrin into equilibrium with Its corresponding alkoxide... 

Base promoted cyclization of vicinal halohydrms (Section 16 10) This reaction is an intramolecu lar version of the Williamson ether synthesis The alcohol function of a vicinal halohydrin is con verted to its conjugate base which then displa ces halide from the adjacent carbon to give an epoxide... 

Halohydrin (Section 6 17) A compound that contains both a halogen atom and a hydroxyl group The term is most often used for compounds in which the halogen and the hydroxyl group are on adjacent atoms vicinal halohydrins) The most commonly encountered halohydrins are chlorohydnns and brornohydrins... 

Electrochemical Process. Applying an electrical current to a brine solution containing propylene results in oxidation of propylene to propylene oxide. The chemistry is essentially the same as for the halohydrin process. AH of the chemistry takes place in one reactor. Most of the reported work uses sodium or potassium bromide as the electrolyte. Bromine, generated from bromide ions at the anode, reacts with propylene and water to form propylene bromohydrin. Hydroxide generated at the cathode then reacts with the bromohydrin to yield propylene oxide (217—219). The net reaction involves transfer of two electrons ... 

Propylene oxide has found use in the preparation of polyether polyols from recycled poly(ethylene terephthalate) (264), haUde removal from amine salts via halohydrin formation (265), preparation of flame retardants (266), alkoxylation of amines (267,268), modification of catalysts (269), and preparation of cellulose ethers (270,271). 

Addition of chlorine or bromine in the presence of water can yield compounds containing haUde and hydroxyl on adjacent carbon atoms (haloalcohols or halohydrins). The same products can be obtained in the presence of methanol (13) or acetic acid (14). As expected from the halonium ion intermediate, the addition is anti. As expected from Markovnikov s rule, the positive halogen goes to the same carbon that the hydrogen of a protic reagent would. 

Uses. /-Butyl hypochlorite has been found useful in upgrading vegetable oils (273) and in the preparation of a-substituted acryflc acid esters (274) and esters of isoprene halohydrins (275). Numerous patents describe its use in cross-linking of polymers (qv) (276), in surface treatment of mbber (qv) (277), and in odor control of polymer latexes (278). It is used in the preparation of propylene oxide (qv) in high yield with Httle or no by-products (269,279). Fluoroalkyl hypochlorites are useful as insecticides, initiators for polymerizations, and bleaching and chlorinating agents (280). 

With Acyl Halides, Hydrogen Halides, and Metallic Halides. Ethylene oxide reacts with acetyl chloride at slightly elevated temperatures in the presence of hydrogen chloride to give the acetate of ethylene chlorohydrin (70). Hydrogen haUdes react to form the corresponding halohydrins (71). Aqueous solutions of ethylene oxide and a metallic haUde can result in the precipitation of the metal hydroxide (72,73). The haUdes of aluminum, chromium, iron, thorium, and zinc in dilute solution react with ethylene oxide to form sols or gels of the metal oxide hydrates and ethylene halohydrin (74). 

The reductive elimination of halohydrins provides a means of introduction of double bonds in specific locations, particularly as the halohydrin may be obtained from the corresponding a-halo ketone. This route is one way of converting a ketone into an olefin. (The elimination of alcohols obtainable by reduction has been covered above, and other routes will be discussed in sections IX and X.) An advantage of this method is that it is unnecessary to separate the epimeric alcohols obtained on reduction of the a-bromo ketone, since both cis- and tran -bromohydrins give olefins (ref. 185, p. 251, 271 cf. ref. 272). Many examples of this approach have been recorded. (For recent examples, see ref. 176, 227, 228, 242, 273.) The preparation of an-drost-16-ene (123) is illustrative, although there are better routes to this compound. 

The high degree of stereoselectivity associated with most syntheses and reactions of oxiranes accounts for the enormous utility of these systems in steroid syntheses. Individual selectivity at various positions in the steroid nucleus necessitates the discussion of a collection of uniquely specific reactions used in the synthesis of steroidal epoxides. The most convenient and generally applicable methods involve the peracid, the alkaline hydrogen peroxide and the halohydrin reactions. Several additional but more limited techniques are also available. 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

Alcoholic potassium hydroxide or sodium hydroxide are normally used to convert the halohydrins to oxiranes. Other bases have also been employed to effect ring closure in the presence of labile functional groups such as a-ketols, e.g., potassium acetate in ethanol, potassium acetate in acetone or potassium carbonate in methanol.However, weaker bases can lead to solvolytic side reactions. Ring closure under neutral conditions employing potassiunT fluoride in dimethyl sulfoxide, dimethylformamide or A-methyl-pyrrolidone has been reported in the patent literature. 

The primary product of hypohalite photolysis is a 1,5-halohydrin, the stability of which increases on passing from iodo- to bromo- to chloro-hydrins. If spontaneous elimination of hydrogen halide does not occur, the halohydrins can be converted into tetrahydrofurans by base treatment. In several instances it has been possible to isolate the intermediate... 

Bartonand Wolft achieved a similar transformations after introduction of a 5,6-double bond by zinc reduction of a 5,6-halohydrin. 

The 10l -acetoxy group can be red actively removed with zinc and acetic acid or chromous chloride to give I9-norsteroids in high yield. Thermal elimination (boiling tetralin) of acetic acid from the crude 10)5-acetoxy-A -3-ketone or treatment with methanolic alkali leads to aromatization of ring A. Estrone alkyl ethers are formed from 10)5-acetoxy-19-nor-A -androstene-3,17-dione by treatment with alcohols and perchloric acid. Similar aromatizations are observed with 5,10-oxido, 5,10-dihydroxy, 5,10-halohydrins or 5,10-dihalo-3-ketones. ... 

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