Electrophile-nucleophile approach

There are very few reactions of real synthetic significance which proceed via condensation of two 1,3-electrophile-nucleophile species. Probably the most important of this latter type of reaction is the synthesis of pyrazines by self-condensation of an a-acylamino compound to the dihydropyrazine followed by aromatization (equation 132). The a-acylamino compounds, which dimerize spontaneously, are normally generated in situ, for example by treatment of a- hydroxy carbonyl compounds with ammonium acetate or by reduction of a-azido, -nitro or -oximino carbonyl compounds. Cyclodimerization of a-amino acids gives 2,5-dioxopiperazines (equation 133), many derivatives of which occur as natural products. Two further reactions which illustrate the 1,3-electrophile-nucleophile approach are outlined in equations (134) and (135), but su i processes are of little general utility. 

Before seeing how electrophilic aromatic substitutions occur, let s briefly recall what we said in Chapler 6 about electrophilic alkene additions. When a reagent such as HCl adds to an alkene, the electrophilic hydrogen approaches the p orbitals of the double bond and forms a bond to one carbon, leaving a positive charge at the other carbon. This carbocation intermediate then reacts with the nucleophilic Cl- ion to yield the addition product. 

Fig. 9. Asymmetry of interactions of C-S-C groups. Nucleophiles approach the C-S-C bond in its plane, while electrophiles approach nearly perpendicular to this plane, (a) General view, (b) view along C-S-C plane, and (c) view onto C-S-C plane.

The radiosynthesis starts with the nucleophilic F-fluorination of 2-benzyloxy-4-formyl-A/,A/,A/-trimethylanilinium trifluoromethanesulfonate or 5-benzyloxy-2-nitrobenzaldehyde. Subsequent condensation with nitroethane yielded the corresponding 2-nitro-1-propanol derivatives. Reduction of the nitro moiety and deprotection provided the four stereoisomers of " F-labeled 2-amino-1-(4-fluoro-3-hydroxyphenyl)-1-propanol and 2-amino-1-(2-fluoro-5-hydroxyphe-nyl)-1-propanol, respectively. 4-p F]FMR was isolated from the 2-amino-1-(4-fluoro-3-hydroxyphenyl)-1-propanol stereoisomer mixture via semipreparative HPLC and additional chiral HPLC for enantiomeric resolution. In a similar manner enantiomeric pure 6-p F]FMR was obtained. From a synthetic point of view, 4-p F]FMR appeared to be the more promising candidate for PET investigations due to higher radiochemical yields. The main advantage of the nucleophilic approach over the electrophilic methods is the obtained high specific radioactivity (56-106 GBq/pmol) that is desired for safe use in humans with tracer doses far beyond the pharmacological level [173]. 

Aldehydes are more reactive than ketones. Two factors that make aldehydes more reactive than ketones are electronic and steric effects. Ketones have two alkyl groups, whereas aldehydes have only one. Because alkyl groups are electron donating, ketones have their effective partial positive charge reduced more than aldehydes. The electrophilic carbon is the site where the nucleophile approaches for reaction to occur. In ketones, two alkyl groups create more steric hindrance than one in aldehydes. As a result, ketones offer more steric resistance toward the nucleophilic attack than aldehydes. 

In the dihydronaphthalene series, the selective exo addition of the nucleophile and exo addition of the electrophile (steric approach) results in exclusive formation of the c/r-ot,3-disubstituted tetralin (78 equation 53).128... 

As shown in Scheme 4.1, during an Sn2 reaction at sp3-hybridized carbon the nucleophile approaches the electrophile from the side opposite to the leaving group. Hence, if the remaining three substituents at the electrophilic carbon are large, the nucleophile will have to overcome repulsive forces, especially so if the nucleophile also is large. This steric repulsion is believed to be the main reason for the strong dependence of bimolecular substitution rates on the structure of simple alkyl halides (Table 4.1). 

This model assumes nonperpendicular attacks (more precisely acute angles of attack, cf. p. 172) and staggered conformations. As the electrophile now approaches the double bond near its center, the inside position becomes the more hindered position, contrary to the case of nucleophilic addition to carbonyls ... 

The first two (Acheson and Paquette) are still very good texts even today. Of the more recent pair, both are warmly recommended. Joule and Smith is possibly a more introductory text than Gilchrist, which contains many journal references and is pitched at the advanced undergraduate/postgraduate level. See Gilchrist for a discussion of the nucleophilic/electrophilic fragment approach to heterocyclic synthesis. 

This effect on the rate is another example of steric hindrance. When the nucleophile approaches the back side of the electrophilic carbon atom, it must come within bonding distance of the back lobe of the C—X sp3 orbital. If there are two alkyl groups bonded to the carbon atom, this process is difficult. Three alkyl groups make it impossible. Just one alkyl group can produce a large amount of steric hindrance if it is unusually bulky, like the ferf-butyl group of neopentyl bromide. 

Azides are formed by the reaction of lithio derivatives with />-toliicncsulfonyl azide, and these in turn can be converted into the corresponding amino compounds by a variety of reductive procedures. Nitro compounds are available by a novel reversal of the general pattern of reaction with electrophiles. This approach requires the initial conversion of the lithio compound into an iodonium salt followed by reaction with nitrite ion. This is illustrated by the preparation of 3-nitrothiophene (Scheme 145). Other nucleophiles, such as thiocyanate ion which yields the 3-thiocyanate, can be employed. The preparative significance of these reactions is again that products not accessible by electrophilic substitution can be obtained. 

We can also explain inversion of configuration in the Sn2 reaction by looking at the frontier orbitals, but it is a much weaker explanation. The appropriate frontier orbitals will be the HOMO of the nucleophile and the LUMO of the electrophile. Taking the orbitals of methyl chloride in Figs 1.45 and 1.47, we can see the LUMO is the [Pg.155]

The 8, 2 reaction always produces 100% inversion of configuration at the electrophilic carbon. Thus, as shown in Example 3.3, the nucleophile approaches the electrophilic carbon on the side opposite the leaving group (there is a 180° angle between the line of approach of the nucleophile and the bond to the leaving group). 

Since the nucleophilic addition reactions consist of two distinct stages, the stereochemistry of each stage has to be considered. On the basis of the scarce amount of data available, it seems that nucleophiles, like electrophiles, approach bicyclobutane from an equatorial direction. This is an expected path since, viewed as an Sj 2 reaction, the nucleophile approaches the substrate anti to the leaving group (the central bond). This has been experimentally demonstrated by the reaction of thiolate anions with 38. In these reactions, RS was found to assume only an endo position (equation 77) . This was also... 

There was no evidence of anisotropy (preferential angle of approach) of C-F- -H-0 interactions, unlike the the anisotropy observed for C-Cl, C-Br, and C-I interactions in a similar type of analysis,for which it was found that electrophiles approach carbon-halogen bonds at an angle of about 100° (nearly perpendicularly), nucleophiles approach at about 165° (almost directly). 

To predict which of the two alkyne carbons, C or C, HNC will preferentially attack, one now invokes the local HSAB principle [119], which says that interaction is favored between electrophile/nucleophile (or radical/radical) of most nearly equal softness. The HNC carbon softness of 1.215 is closer to the softness ofC (1.102) than that of (0.453) of the alkyne, so this method predicts that in the reaction scheme above the HNC attacks C in preference to C, i.e. that reaction should occur mainly by the zwitterion A. This prediction agreed with that from the more fundamental approach of calculating the activation energies as the difference of ttansition state and reactant energies. This kind of analysis worked for -CH3 and -NH2 substituents on the alkyne, but not for -F. 

A nucleophile is attracted to the partially positively charged carbon (an electrophile). As the nucleophile approaches the carbon and forms a new bond, the carbon-halogen bond breaks heterolytically (the halogen takes both of the bonding electrons). 

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