Factor 1—The Electrophile Substrate

The electrophile is the compound being attacked by the nucleophile. In substitution and elimination reactions (which we will see in the next chapter), we generally refer to the electrophile as the substrate. 

Remember that carbon has four bonds. So, other than the bond to the leaving group, the carbon atom that we are attacking has three other bonds  

The question is, how many of these groups are alkyl groups (methyl, ethyl, propyl, etc.) We represent alkyl groups with the letter R. If there is one alkyl group, we call the substrate primary (1°). If there are two alkyl groups, we call the substrate secondary (2°). And if there are three alkyl groups, we call the substrate tertiary (3°)  

In an Sn2 reaction, aUcyl groups make it very crowded at the electrophilic center where the nucleophile needs to attack. If there are three alkyl gronps, then it is virtually impossible for the nucleophile to get in and attack (this is an argument based on sterics)  

But SnI reactions are totally different. The first step is not attack of the nncleo-phile. The first step is loss of the leaving group to form the carbocation. Then the nncleophile attacks the carbocation. Remember that carbocations are trigonal planar, so it doesn t matter how big the gronps are. The groups go out into the plane, so it is easy for the nucleophile to attack. Sterics is not a problem. 

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In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionahzed P-amino alcohols 35 [29, 30], The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30], The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophilic substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-armnation reaction, which selectively forms 36. 

Aromatic substrates are by far the most commonly used substrates in the rapidly expanding area of photoinduced electron transfer [1,2]. This is obviously due to the favourable location of the frontier molecular orbitals in such compounds. The same factor facilitates the formation of electron transfer donor-acceptor (EDA) complexes both in the ground state (these possibly are intermediates in some thermal reactions, e.g. selected electrophilic substitutions), and in the excited state (exciplexes). 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

Hi) High sensitivity to conjugative -polar effects. The great positional and substrate selectivity of biphenyl and naphtalene may be in principle due to two separate causes either to conjugative polar effects as for electrophilic reactions (Scheme 3) or to resonance stabilization of the intermediate radicals (Scheme 4). The first effect was considered much more important for two reasons the high selectivity shown by aromatic compounds such as phenol, anisole, acetanilide and the fact that, in the absence of marked polar effects, as in homolytic phenylation of biphenyl, the partial rate factor of the para position has a rather low value (2.5), not differing greatly from those of the ortho (2.1) and meta (1.0) positions 2). 

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