Halogen, introduction

Aromatic compounds may be chlorinated with chlorine in the presence of a catalyst such as iron, ferric chloride, or other Lewis acids. The halogenation reaction involves electrophilic displacement of the aromatic hydrogen by halogen. Introduction of a second chlorine atom into the monochloro aromatic stmcture leads to ortho and para substitution. The presence of a Lewis acid favors polarization of the chlorine molecule, thereby increasing its electrophilic character. Because the polarization does not lead to complete ionization, the reaction should be represented as shown in equation 26. 

Despite several attractive features in this method of direct halogen introduction and the obvious applications in the synthesis of deoxy sugars, its uses have not been further exploited by other groups of workers. Some new related methods have become available which reportedly eliminate the difficulties previously encountered such as rearrangement, unreactivity due to steric hindrance, and phosphonate ester formation. The reaction is based on the observation (28) that triethylphosphine reacts with ethanol and carbon tetrachloride to give ethyl chloride, chloroform, and triethylphosphite. In a new adaptation (76, 77) of this... 

Chlorobutyl (CIIR) and bromobutyl (BIIR) are modified types containing 1.2% wt of chlorine or bromine, the isoprene unit being the site of halogenation. Introduction of the halogen gives greater cure flexibility, and enhanced cure compatibility in blends with other diene rubbers. It also confers increased adhesion to other rubbers and metals. 

In the United States also, 5,6-diarylpyridazinone derivatives have been studied extensively as potential antihypertensive agents [374-377]. From experiments with spontaneously hypertensive rats and the deoxycorticosteroid model of hypertension, it turned out that substitution of the phenyl rings by halogen, introduction of an electron-attracting group (like acetyl or... 

Indanth rones. The blue indanthrone was the first synthetic vat dye of the anthra-quinone series. Because of its excellent fastness and bright colors it has remained the most important vat dye for a long time despite its low resistance to chlorine. Its chlorine resistance can be improved somewhat by post-halogenation. Introduction of hydroxy or amino groups shifts the shade to green. 

As discussed earlier (see Section 7.2), electrophilic monochlorination, -bromination and -iodination of imidazoles and 1-substituted imidazoles is difficult because of the great propensity of the molecules to polyhalogenate. Methods have, however, been developed to achieve selective halogen introduction on all ring sites. Fluorination is a special case (see below). 

The direct introduction of a halogen atom (usually bromine) by means of V-haloamine (generally iV-bromosuccinimide) in the allyl position is known as the Wohl-Ziegler reaction ... 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

The enol content of a carboxylic acid is far less than that of an aldehyde or ketone and introduction of a halogen substituent at the a carbon atom requires a different set... 

Nitration and halogenation of furfural occurs under carehiUy controlled conditions with introduction of the substituent at the open 5-position (24,25). Nitration of furfural is usually carried out in the presence of acetic anhydride, resulting in the stable compound, 5-nitrofurfuryhdene diacetate (26,27). The free aldehyde is isolated by hydrolysis and must be used immediately in a reaction because it is not very stable. 

A significant advance in flame retardancy was the introduction of binary systems based on the use of halogenated organics and metal salts (6,7). In particular, a 1942 patent (7) described a finish for utilizing chlorinated paraffins and antimony(III) oxide [1309-64-4]. This type of finish was invaluable in World War II, and saw considerable use on outdoor cotton fabrics in both uniforms and tents. 

Polymerization. The first successful polymerizations of VDE in aqueous medium using peroxide initiators at 20—150°C and pressures above 30 MPa were described in a patent issued in 1948 (73). About a year later, the first copolymerizations of VDE with ethylene and halogenated ethylenes were also patented (74). After a hiatus of over 12 years a commercially feasible process was developed and PVDE was ready for market introduction (2). 

Oxidation of N -substituted pyrazoles to 2-substituted pyrazole-l-oxides using various peracids (30) facilitates the introduction of halogen at C, followed by selective nitration at C. The halogen atom at or is easily removed by sodium sulfite and acts as a protecting group. Formaldehyde was... 

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Introduction of a 3-bromosubstituent onto thiophene is accompHshed by initial tribromination, followed by reduction of the a-bromines by treatment with zinc/acetic acid, thereby utilizing only one of three bromines introduced. The so-called halogen dance sequence of reactions, whereby bromothiophenes are treated with base, causing proton abstraction and rearrangement of bromine to the produce the most-stable anion, has also been used to introduce a bromine atom at position 3. The formation of 3-bromotbiopbene [872-31-1] from this sequence of reactions (17) is an efficient use of bromine. Vapor-phase techniques have also been proposed to achieve this halogen migration (18), but with less specificity. Table 3 summarizes properties of some brominated thiophenes. 

It is possible to introduce sulfonic acid groups by alternative methods, but these ate Htde used in the dyes industry. However, one worth mentioning is sulfitation, because it provides an example of the introduction of a sulfonic acid group by nucleophilic substitution. The process involves treating an active halogen compound with sodium sulfite. This reaction is used in the purification of m-dinitrohen7ene. 

Substituted Anthraquinones. Commercially important blue disperse dyes are derived from 1,4,5,8-substituted anthraquiaones. Among them, diaminodihydroxyanthraquiaone derivatives are most important in view of their shades and affinity. Representative examples are Cl Disperse Blue 56 [31810-89-6] (11) Cl 63285) (126), and Cl Disperse Blue 73 (113) (115). Introduction of a halogen atom ortho to the amino group improves affinity and lightfastness. 

Reductive ring closure with thionyl chloride led to the introduction of a chloro group in the 5-position. When the 5-position was blocked by a substituent, halogen attack occurred in the 7-position. The mechanism is shown in Scheme 177 (67AHC(8)277>. 

While melamine is widely used in flexible foams as a fire-retardant, trichlorphenyl phosphate has been the preferred agent for use in rigid foams. However, the introduction of specifications stipulating halogen-free additives has led to a search for alternatives such as halogen-free phosphorus esters, red phosphorus and ammonium polyphosphate. 

The specific introduction of halogen has been described in the previous section. Selective methods for dehydrohalogenation are described below. 

Probably the most widely used method for the introduction of an oxygen function at C-21 involves the bromination of a 17a-hydroxy-20-ketopregnane, followed by displacement of the halogen by acetate ... 

It should be noted that these were the first examples of the Cu-catalyzed crosscoupling of arylhalides with terminal acetylenes. The authors (71IZV1764) carried out the acetylenic condensation with unreactive 4-iodo-l,3,5-trimethylpyrazole, a compound in which the halogen atom is not only found in a position more unfavorable for replacement, but is also further deactivated by the introduction of electron-donor methyl groups (Scheme 40). 

The methyl group of a methyl ketone is converted into an a ,a ,a -trihalomethyl group by three subsequent analogous halogenation steps, that involve formation of an intermediate enolate anion (4-6) by deprotonation in alkaline solution, and introduction of one halogen atom in each step by reaction with the halogen. A... 

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