Bromine soft electrophile

The product of this reaction, the sulfenyl chloride, is also a good soft electrophile towards carbon atoms, particularly towards alkenes. The reaction is very like bromination with a three-membered cyclic sulfonium ion intermediate replacing the bromonium ion of Chapter 20. The reaction is stereo-specific and anti. 

Acid anhydrides, being carbonyl electrophiles with polarized C=0 bonds, respond to charge tensity (they are hard electrophiles) and react well with oxygen nucleophiles. Bromine, by - jntrast, is uncharged and unpolarized (it is a soft electrophile) and reacts well with neutral nucleophiles such as alkenes (Chapter 20). Each electrophile reacts regioselectively with the part of --.e enol that suits it best. 

For example, the reaction between the soft nucleophile, e g. an alkene, and a soft electrophile, such as a bromine molecule, is shown in the following reaction. 

As the bromine molecule approaches the n electrons, they induce a temporary dipole in the electron cloud of the bromine. This is easily done, because the outer electrons on the bromine molecule are a long way from the two positive nuclei, and so are held less firmly than if they were more closely bound. In other words, the bromine molecule is a soft electrophile, because its electron cloud may be easily distorted. Note that all temporarily induced dipolar interactions are attractive in nature, and so facilitate the further approach of the reacting species. 

This analysis of the simple addition of an electrophilic bromine molecule to a symmetrical alkene or alkyne has highlighted many points. First, there is the induction of a temporary dipole of the soft electrophile by the n electrons of the carbon/carbon double bond. Second, there is the heterolytic fission of the bromine molecule, and the subsequent formation of the cyclic bromonium ion. Third, this cyclic intermediate places certain restrictions on the potential line of attack for the second reagent, and so controls the structural and stereochemical consequences for the product. 

To take a very simple example, a nucleophile like the hydroxide ion is hard at least partly because it has a charge, and because it is based on a small and electronegative element. Accordingly, it reacts much faster with a hard electrophile like a proton than with a soft electrophile like bromine. On the other hand, an alkene is a very soft nucleophile, at least partly because it is uncharged and has a high-energy HOMO. Thus it reacts much faster with an electrophile which... 

Although detailed mechanistic studies are lacking, HSAB considerations appear to favor the first non-redox mechanism, where sulfur, a soft nucleophile, attacks bromine, a soft electrophile. 

OCH3 and NH3, give exclusive attack at the hard electrophilic centres, i.e. C—F, whereas soft nucleophiles displace bromine. This is further evidence for the importance of ion-dipole interactions, regarding attack at C—F bonds. Reactions of perfluoro-quinoline and -isoquinoline with hard and soft nucleophiles have also revealed a sensitivity towards a change in orientation of attack with the nature of the nucleophile [114] (Figure 9.42). 

It is in chloro- and bromoacetylenes particularly that sp carbon (C , Q) and halogen compete for the nucleophile (Table 6). HSAB theory has been used to rationalize the variations in the site of attack with changes in the nucleophile " . Bromine and chlorine are considered to be softer electrophilic centres than sp carbon. As the softness of the nucleophile increases there is an increasing amount of attack on these halogen centres, e.g. MeS gives 92% attack on bromine, while hard MeO produces only 5% attack on bromine in phenylbromoacetylene , soft S- gives 33% attack on chlorine while hard OH attacks only sp carbon in l-chloro-2-(2-thienyl) acetylene (Table 6) . 

The synthesis of thiazoles 43 adds an element of regioselectivity as the thioamide has soft (S orbital controlled) andhard (N charge controlled) nucleophilic sites anditis essential to differentiate equally clearly between the two electrophilic centres on the carbonyl part of the molecule. We need to know that a thioamide will react with an a-haloketone 48 X = Cl, Br so that the hard nitrogen atom attacks the ketone and the soft sulfur atom attacks the saturated carbon atom. Thus the simple non-steroidal anti-inflammatory drug Fentiazac 50 is made from thiobenzamide 51 and the simple bromoketone 52, made in turn by bromination of the ketoacid. The synthesis is just that.3... 

Alkenes 4.24, with a n orbital as the HOMO and no charge, are inherently soft nucleophiles, and their nucleophilicity ought to have some relationship to the energy of their HOMOs. The relative rates of attack by different alkenes have been measured for such electrophiles as bromine, peracids, sulfenyl halides, electrophilic 1,3-dipoles (Chapter 6), metal cations (Hg2+, Ag+) and boranes. These electrophiles fall into two groups those like bromine, peracid and sulfenyl halides that show a correlation between the rate and the ionisation potential of the alkene, and those like 1,3-dipoles, metal cations and boranes, that show significant discrepancies.263 The first group show little sign of steric effects, since the more substituted alkenes, with the... 

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