Nucleophilic attachment

The behavior of such activated halides as alkylating agents under Friedel-Crafts conditions expands the scope of the synthesis. Aluminum chloride enhances the electrophilic character of the a,/S-unsaturated carbonyl system and permits the nucleophilic attachment of the aromatic addendum (Y ) to the carbon bearing the positive charge, with displacement of halogen [Eq. (5)]. Thus,... 

So far, only reactions in which the internal nucleophile is tethered to the nitrogen atom of the A -acyliminium ion have been discussed, however, cyclizations with nucleophiles attached to other positions are also possible. If the nucleophile is connected to the carbon atom adjacent to the carbonyl group, bridged azabicycloalkane derivatives are obtained in high yield by using the more reactive allyl- or propargylsilanes. 

Reactions of this type are mostly performed with internal nucleophiles attached to the carbon atom adjacent to the iminium nitrogen, thus leading to tropane-like azabicyclic systems. Both allyl- and propargylsilanes, activated and unactivated alkenes, and ketones have been successfully used as nucleophiles. The products 1 and 2 are also obtained via two consecutive C —C bond-forming reactions in a single operation. 

The chloromethylated polymers are very reactive substrates for nucleophilic attach further elaboration can be accomplished under homogeneous conditions In aprotlc solvents, or under heterogeneous conditions In the presence of phase transfer catalysts. The following examples are representative of approaches to functionalized condensation polymers via chloromethylated Intermediates. 

In case of optically active alkyl halides, the product formed as a result of Sn2 mechanism has the inverted configuration as compared to the reactant. This is because the nucleophile attaches itself on the side opposite to the one where the halogen atom is present. When (-)-2-bromooctane is allowed to react with sodium hydroxide. (+)-octan-2-ol is formed with the -OH group occupying the position opposite to what bromide had occupied. 

The Sn(AE) mechanism consists of the initial addition (A) of the nucleophile (attachment) to the carbon atom bearing the potential leaving group, followed by the elimination (E) of the latter.85 It is analogous to the one usually occurring in the nucleophilic substitution of nitro-activated aromatic substrates. 

A well understood case is that of quinoline reaction at position 2 is kinetically favored as compared with reaction at position 4, but the adduct from the latter is thermodynamically more stable. This situation, where the site of attack leading to the more stable adduct is the y position, is analogous with those regarding the formation of Meisenheimer adducts from benzene and pyridine derivatives and RCT nucleophiles. Presumably, with quinoline kinetic control favors the position that is more strongly influenced by the inductive effect of the heteroatom. The fact that position 2 of quinoline is the most reactive toward nucleophilic reagents is probably related to the lower 71-electron density at that position.123 However, the predominance of the C-4 adduct at equilibrium can be better justified by the atom localization energies for nucleophilic attachment at the different positions of quinoline. Moreover, both 7t-electron densities and atom localization energies indicate position 1 of isoquinoline to be the most favored one for nucleophilic addition. 

Nitropyrimidine, its 2- and 4-methoxy, and 2,4- and 4,6-dimethoxy derivatives react with acetone in the presence of potassium hydroxide to yield the potassium salts of the anionic adducts 74 and 75, with structures elucidated by spectral ( H-NMR, IR, and UV-visible) methods. The nucleophilic attachment was found to occur only at CH positions, and when there was a choice between 2- and 4(6)-positions, the latter was preferred.125,126 An adduct of the kind corresponding to structure 75 was also obtained by using the conjugate base of acetophenone. The adducts can be converted to the corresponding CH3COCH2- or PhCOCH2-substituted pyrimidines by oxidation, either directly or via the related dihydropyrimidine derivatives.127... 

Quantitative studies of these reactions would be desirable in order to understand the factors controlling the regioselectivity of nucleophilic attachment. 

Experimental precautions are required for NMR measurements in this group because the adducts rapidly undergo ring opening. The NMR spectra of the selenophene adducts in solution are similar to those of the corresponding thiophene adducts. The H-NMR data for adducts 142-145, as obtained from dinitro and cyanonitroselenophene derivatives, are reported in Table XXI. It is of interest that, unlike 2-cyano-4-nitrothiophene, its selenophene analog is converted to the anionic a-adduct by nucleophilic attachment at the unsubstituted C-5 position without any competition from a reaction at the CN side chain.169... 

The high heat of formation of the N3 cation ( 350 kcal/mol) makes it very attractive as a component of high energy density materials (HEDMs). However, its large vertical electron affinity (vEA) of 6.1 eV poses a problem So far, the preparation of only NsAsFg, N ShF, and NjSb2Fu has been reported. The oxidation of Br2 (IP 10.5 eV) by N SbFj shows that N3 is also susceptible to nucleophilic attack by Lewis bases. Calculations on NjNj show that such a crystal may exist, but nucleophilic attach of the anion is a likely side-reaction. We think that less electronegative derivatives of N3 may be less sensitive to both reduction and nucleophilic attack. 

The first reported synthesis of the raloxifene scaffold was based on the coupling of carboxylic acid fragment 12 with benzothiophene nucleus 13. The main carbon-carbon bond formation was thus achieved via nucleophilic attach of the benzothiophene through its C(3) position on the activated carbonyl of 12. The final step in the synthesis was the cleavage of both methyl ethers to unmask the requisite hydroxyls.48,49... 

This means that the product has the electrophile attached to the carbon that would be less stable as a carbocation and the nucleophile attached to the carbon that would be more stable as a carbocation. Later, we will encounter exceptions to Markovnikov s rule. However, these exceptions are still in accord with this mechanistically based rule. 

The mercurinium ion reacts with water in the same manner as the bromonium ion. The nucleophile attaches to the more highly substituted carbon from the side opposite the leaving mercury. Because a free carbocation is not involved in the mechanism, the reaction is not prone to reairangement. 

Table 11.4 summarizes the reactions in which the electrophile and the nucleophile are linked in the same molecule (hydroboration, hydroxylation, ozonolysis). These additions occur in a concerted manner. The regiochemistry of the addition is such that the nucleophile attaches to the carbon that would be more stable as a carbocation and the addition occurs with syn stereochemistry. 

An interesting use of the bond e disconnection for the synthesis of perfluoro aziridines was reported <1999CC47>. Treatment of perfluoro imine 65 with an excess of PhLi provides the aziridine 67 in good yield (Equation 20). This reaction is believed to go through intermediate 66 after an initial addition of 2 equiv of PhLi. A subsequent nucleophilic attach of the nitrogen anion to displace a fluorine results in aziridine ring formation. The ease with which this strained system forms is attributed to relief of the 1,3-diaxial interactions found in intermediate 66. In addition, an X-ray structure of aziridine 67 was obtained. 

The MO data for cyano-, formyl- and ethynylacetylene (Figure 6) fail to indicate the correct positional isomer. Instead of C, attack, C/a or Michael addition products are the rule for these terminal alkynes (equations 32-34). Of course, when nucleophilic attachment occurs at C j, the substituents are capable of stabilizing incipient... 

In contrast to the major course of addition in ethynyl ethers, the predominant mode in ethynyl thioethers is nucleophilic attachment to Cp, as in equation (40). . . Arens accounted for such differences in orientation by proposing that... 

Fig. 7.13. Relief maps of — for S2N2, and The arrows indicate the direclion of nucleophilic attachment to the cations by the fluorides of the anions in the crystal.

Demchenko et al. developed 1-5-benzoxazolyl (SBox) mannoside 23-25 as potent donors for the synthesis of -mannoside [40]. They demonstrated that an acyl or thiocarbamoyl group at the C-4 position gave a favorable effect, possibly by participating to the C-1 position. Nucleophilic attachment of an acceptor occurs predominantly from the y0-face [40] (O Scheme 15). 

Becau.se the El proces.s involves the same rale-determining step a.s the S. l reaction, its kinetics are the same first order. EJ elimination almost always accompanies SnI substitution. The difference is simple In S l, the nucleophile attaches to the cationic carbon in El, it attaches to and removes a proton. Thus nucleophiles that are very weak bases will favor S l, with El contributing more and more as basicity increases. For the practical piirpo.ses of synthesis, the prc.sence of the El "side reaction can limit the usefulness of SnI siihsliliition,... 

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