Iodination, electrophilic, kinetics

The addition of iodine electrophiles, fert-butyl hypoiodite (t-BuOI) in the presence of BF3, acetyl hypoiodite (AcOI), iodine monochloride (IC1) and iodine monobromide (IBr), to 1,3-butadiene gives always, under ionic conditions, mixtures of 1,2- and 1,4-Markovnikov adducts (equation 57). These mixtures are the kinetic products, since rearrangement to the thermodynamically stable products occurs under the appropriate conditions86. 

When unsubstituted, C-5 reacts with electrophilic reagents. Thus phosphorus pentachloride chlorinates the ring (36, 235). A hydroxy group in the 2-position activates the ring towards this reaction. 4-Methylthiazole does not react with bromine in chloroform (201, 236), whereas under the same conditions the 2-hydroxy analog reacts (55. 237-239. 557). Activation of C-5 works also for sulfonation (201. 236), nitration (201. 236. 237), Friede 1-Crafts reactions (201, 236, 237, 240-242), and acylation (243). However, iodination fails (201. 236). and the Gatterman or Reimer-Tieman reactions yield only small amounts of 4-methyl-5-carboxy-A-4-thiazoline-2-one. Recent kinetic investigations show that 2-thiazolones are nitrated via a free base mechanism. A 2-oxo substituent increases the rate of nitration at the 5-position by a factor of 9 log... 

In deducing from the resulting kinetic equation the nature of the electrophile and how it is produced it is important to represent all the reagents present in terms of the species which they may produce. In this way it is possible to eliminate many negative or fractional orders in reagent and generally obtain a simpler kinetic equation. For example, the observed rate law in the uncatalyzed iodination of aniline can be written21,22 as... 

Iodine acetate also has been proposed331 as the electrophile in the peroxyacetic catalysed-iodination of benzene in acetic acid at 50 °C, which obeys the kinetic equation... 

The kinetics of iodination of aniline and / -toluidine by iodine in acidified aqueous methanol have been determined at various solvent compositions and temperatures. It was deduced that HOI was the effective electrophile under the reaction conditions. 

Formation of a highly electrophilic iodonium species, transiently formed by treatment of an alkene with iodine, followed by intramolecular quenching with a nucleophile leads to iodocyclization. The use of iodine to form lactones has been elegantly developed. Bartlett and co-workers216 reported on what they described as thermodynamic versus kinetic control in the formation of lactones. Treatment of the alkenoic acid 158 (Scheme 46) with iodine in the presence of base afforded a preponderance of the kinetic product 159, whereas the same reaction in the absence of base afforded the thermodynamic product 160. This approach was used in the synthesis of serricorin. The idea of kinetic versus thermodynamic control of the reaction was first discussed in a paper by Bartlett and Myerson217 from 1978. It was reasoned that in the absence of base, thermodynamic control could be achieved in that a proton was available to allow equilibration to the most stable ester. In the absence of such a proton, for example by addition of base, this equilibration is not possible, and the kinetic product is favored. 

The choice of the solvent and of the electrophile is very important since the reaction can be carried out under kinetic or thermodynamic control. The possibility of equilibrating a cyclic intermediate strongly influences the regio- and stereochemistry of the reaction. The presence of a base in an aqueous medium generally results in kinetic control of the cyclization process18, while reversible conditions are favored by iodine in acetonitrile19. In addition, A -iodosuccin-imide in chloroform, iodine in chloroform and iodine in tetrahydrofuran/pyridine are considered to give cyclizations under kinetic control. On the other hand, the use of AT-bromosuccin-imide or bromine affords lower selectivity. 

The distribution rates for iodination of monosubstituted benzene derivatives have been reported. Under conditions of thermodynamic control (elevated temperature), meta substitution is observed. Under conditions of kinetic control (room temperature), a significant preference for para substitution is observed for compounds containing oriha- puru-directing substituent groups. Ortho substitution results when chelation of TTFA with the directing substituent permits intramolecular delivery of the electrophile. For example, methyl benzoate gives almost exclusively or/ho-lhallation (95%). 

The orientation of addition of iodine chloride to butadiyne, however, corresponds to an electrophilic attack. A study of the kinetics of bromination of various mono- and dialkyl-substituted butadiynes has been interpreted in terms of an electrophilic mechanism . The observed rates increased with increasing inductive electron-releasing power of the substituents. However, the effects are small, and under the conditions used (two-fold excess of hydrocarbon) it seems likely that significant polybromination occurred . Marked catalysis by bromide ion was observed and interpreted in terms of electrophilic attack by bromine on a complex of acetylene with Br ... 

A great deal of evidence has accumulated to show that a metal ion in a chelate ring can alter the electron density in a molecule. One method of obtaining quantitative data on such changes in electron density is to compare the rates of electrophilic attack at a point in the unchelated and chelated molecules as, for example, in the iodination of 8-hydroxyquinoline chelates (Section II,A). Another such kinetic study has been carried out on the diazo coupling of 8-hydroxyquinoline-5-sulfonic acid and its zinc(II) chelate with diazotized sulfanilic acid (141)-... 

Copper(I)-catalyzed tandem reaction of isothiocyanates and iodophenols in ionic liquids produced 95 (13JOM(723)137) iodine-mediated electrophilic cychzation of osmabenzene resulted in the isolation and characterization the osmabenzene-fused oxathiole 96 (13AGE9251) and nickel chloride-catalyzed reaaion of aromatic aldehydes with 2-mercaptoethanol produced 97 only as a minor product together with the bis(2-hydroxyethyl)dithioac-etals (13TL5839). Lamivudine 98 and its enantiomer 99 have been efficiently asymmetrically synthesized via enzymatic dynamic kinetic resolution (13CC10376). The deprotection of 1,3-oxathiolanes 100 promoted by a range of bases has been examined (13TL2217). 

This principal reaction mechanism is widely believed to apply to most S Ar reactions irrespective of the electrophilic reagent. There are however a number of experimental observations that indicate exceptions to this mechanism. There are examples of thermodynamically controlled Friedel-Crafts reactions, when using reaction conditions like polyphosphoric acid and elevated temperatures [27,28]. In iodination and some cases of Friedel-Crafts acylation, the last step of the reaction, the proton abstraction, has been shown to have a substantial kinetic isotope effect, which indicates that this step is at least partially rate limiting [29-31]. There are also still open questions regarding the exact nature of the reaction intermediates, and we will focus on these issues in the remaining part of the chapter. 

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