Iodine, substitution reactions

Addition to the Double Bond. Chlorine, bromine, and iodine react with aHyl chloride at temperatures below the inception of the substitution reaction to produce the 1,2,3-trihaLides. High temperature halogenation by a free-radical mechanism leads to unsaturated dihalides CH2=CHCHC1X. Hypochlorous and hypobromous acids add to form glycerol dihalohydrins, principally the 2,3-dihalo isomer. Dehydrohalogenation with alkah to epicbl orobydrin [106-89-8] is ofgreat industrial importance. 

Radical substitution reactions by iodine are not practical because the abstraction of hydrogen from hydrocarbons by iodine is endothermic, even for stable radicals. The enthalpy of the overall reaction is also slightly endothermic. Thus, because of both the kinetic problem excluding a chain reaction and an unfavorable equilibrium constant for substitution, iodination cannot proceed by a radical-chain mechanism. 

The reactivities of the substrate and the nucleophilic reagent change vyhen fluorine atoms are introduced into their structures This perturbation becomes more impor tant when the number of atoms of this element increases A striking example is the reactivity of alkyl halides S l and mechanisms operate when few fluorine atoms are incorporated in the aliphatic chain, but perfluoroalkyl halides are usually resistant to these classical processes However, formal substitution at carbon can arise from other mecharasms For example nucleophilic attack at chlorine, bromine, or iodine (halogenophilic reaction, occurring either by a direct electron-pair transfer or by two successive one-electron transfers) gives carbanions These intermediates can then decompose to carbenes or olefins, which react further (see equations 15 and 47) Single-electron transfer (SET) from the nucleophile to the halide can produce intermediate radicals that react by an SrnI process (see equation 57) When these chain mechanisms can occur, they allow reactions that were previously unknown Perfluoroalkylation, which used to be very rare, can now be accomplished by new methods (see for example equations 48-56, 65-70, 79, 107-108, 110, 113-135, 138-141, and 145-146)... 

Most of the substitution reactions of di-, tetra, and hexa-hydro-carbolines and of their oxo derivatives are similar to those of the parent indole or indolenine derivatives. Nitration and bromination of harma-line (l-methyl-3,4-dihydro-j8-carbolme) are referred to in Section IV, A, 1. Sulfonation and azO COupling ° proceed as expected for indole derivatives. The preparation of chlorinated and iodinated derivatives of 6-nitroharmaline has been reported,but their structures have not been established. 

Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution reactions, but fluorine is too reactive and only poor yields of monofluoro-aromatic products are obtained by direct fluorinafion. Aromatic rings react with CI2 in the presence of FeCl3 catalyst to yield chlorobenzenes, just as they react with Bi 2 and FeBr3. This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the antianxiety agent diazepam, marketed as Valium. 

The reactions are parallel with respect to iodine (fi) and consecutive with respect to iodine-substituted derivatives of L-tyrosine (R). 

Tyrosine may be targeted specifically for modification through its phenolate anion by acylation, through electrophilic reactions such as the addition of iodine or diazonium ions, and by Mannich condensation reactions. The electrophilic substitution reactions on tyrosine s ring all occur at the ortho position to the —OH group (Figure 1.11). Most of these reactions proceed effectively only when tyrosine s ring is ionized to the phenolate anion form. 

Palladium catalyzed cross-coupling reactions of 1-substituted glycals have not only been limited to tributylstannyl derivatives. In fact, the versatility of this approach is significantly enhanced by the fact that C-l zinc-, indium-, or iodine-substituted glycals (easily accesible from glycals, see Scheme 7)... 

Scheme 8.13 and Eqs. 8.6-8.10 reveal that lithiated methoxyallene 42 is sufficiently reactive towards a variety of electrophiles such as alkyl halides [44, 45], ethylene oxide [12c], tosylated aziridine 45 [46], dimethyl disulfide [12b], trialkylstannyl and trialkylsilyl chlorides [47, 48] and iodine [49]. These substitution reactions proceed with excellent regioselectivity and the corresponding a-functionalized products are obtained in good to high yields. An exceptional case was found by treatment of 42 with a guanidinium salt, which led to a 60 40 mixture of a- and y-adducts 50 and 51 (Eq. 8.11) [50],... 

Biirgi studied also a series of five coordinated cadmium complexes, 38, that contain three equatorial sulfur ligands, but in which the fourth and fifth, axial ligands, X and Y, are sometimes iodine, sometimes sulfur, and sometimes oxygen (84). The structural correlations have a clear interpretation in terms of the ligand exchange reaction and are reminiscent of the kind of process that is believed to occur in S 2-type nucleophilic substitution reactions ... 

In a similar way, Kim and Bunnett (1970) demonstrated that the substitution of amino group for iodine in iodotrimethylbenzene proceeds via the ion-radical mechanism, in contrast to the bromo and chloro analogs. The reaction of 5- and 6-halo-l,2,4-trimethylbenzenes with potassium amide in liquid ammonia gives rise to 5- and 6-aminoderivatives. This is the cine-substitution reaction (see Scheme 4.12). 

In a different study, anthracene, phenanthrene, perylene 93 (Fig. 31), and 2,7-di-tert-butylpyrene underwent regioselective oxidative-substitution reactions with iodine(III) sulfonate reagents in dichloromethane to give the corresponding aryl sulfonate esters. The use of [hydroxy(tosyloxy)iodo]benzene, in conjunction with trimethylsilyl isothiocyanate, led to thiocyanation of the PAH nucleus. 

The efficient formation of diaryliodo-nium salts during the electrolysis of arylio-dides has been reported by Peacock and Fletcher [166]. The electroiodination of a 3D-aromatic molecule, dodecahydro-7,8-dicarba-nido-undecaborate has also been reported [167]. The iodination (and bromi-nation) of dimedone has been reported to yield 2-iododimedone, which formally is an electrophilic substitution reaction [123]. In a similar process, the indirect electrochemical oxidation of aliphatic ketones in an alkaline Nal/NaOH solution environment has been shown to yield a,a-diiodoketones, which rapidly rearrange to give unsaturated conjugated esters [168]. Dibenzoylmethane has been converted into dibenzoyliodomethane [169]. Terminal acetylenes have been iodinated in the presence of Nal. However, this process was proposed to proceed via oxidation of the acetylene [170]. 

We have therefore deduced from the formula for the heat of formation of ionic compounds the important rule that the halogens replace one another in the order F2, Cl2, Br2, I2. There are ho known exceptions to this rule. Fluorine displaces chlorine, bromine and iodine from all chlorides, bromides and iodides, while chlorine and bromine displace iodine from all iodides. It is to be expected that the same substitution reactions can take place with the chal-cogens 02, S, Se and Te, and, since the heat of formation of the oxides is, as a rule, greater than that of the sulphides, the reactions of the type... 

The same result can be achieved in one step with m-chloroperoxybenzoic acid and water.719 Overall anti addition can also be achieved by the method of Prevost. In this method the olefin is treated with iodine and silver benzoate in a 1 2 molar ratio. The initial addition is anti and results in a 3-halo benzoate (71). These can be isolated, and this represents a method of addition of IOCOPh. However, under the normal reaction conditions, the iodine is replaced by a second PhCOO group. This is a nucleophilic substitution reaction, and it operates by the neighboring-group mechanism (p. 308), so the groups are still anti ... 

Let us now look at some examples to illustrate what we have discussed so far to get a feeling of how structural moieties influence the mechanisms, and to see some rates of nucleophilic substitution reactions of halogenated hydrocarbons in the environment. Table 13.6 summarizes the (neutral) hydrolysis half-lives of various mono-halogenated compounds at 25°C. We can see that, as anticipated, for a given type of compound, the carbon-bromine and carbon-iodine bonds hydrolyze fastest, about 1-2 orders of magnitude faster than the carbon-chlorine bond. Furthermore, we note that for the compounds of interest to us, SN1 or SN2 hydrolysis of carbon-fluorine bonds is likely to be too slow to be of great environmental significance. 

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