Substitutions in Alkyl Halides

Ligand Substitutions in Alkyl Halides Ligand substitutions in alkyl halides, 

The normal vibrations q and q are related to the shifts of the ions Y and X . The low-frequency part of the inertial polarization of the medium, k(cok co 9 co ), cannot follow these shifts. The high-frequency part of the inertial polarization, /(a / co 1, co )9 adiabatically follows the shifts of the ions Y and X-, and the equilibrium coordinates of the effective oscillators describing this part of the polarization depend on the normal coordinates of the corresponding normal vibrations, viz. /0i(gl), (iof(q )- 

The calculation is performed using Eq. (16) and the model potential energy surfaces 

Neglecting the quantum tail of the inertial polarization of the medium, we can write the outer-sphere contribution to H(6) in the form 

The quantity A h in Eq. (132) is the shift of the equilibrium positions of the protons (at fixed transitional configurations of the other nuclei). 

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Comparison of SnI and Sn2 Mechanisms of Nucleophilic Substitution in Alkyl Halides... 

In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution readily when the ring bears an o- or a p-nitro group. 

Nucleophilic substitutions in alkyl halides catalysed by polypode [116] under liquid-liquid phase-transfer conditions ... 

The well-known action of silver(i) salts on nucleophilic substitution in alkyl halides is another commonplace example of this effect. The silver ion interacts with the halide, thus weakening the carbon-halogen bond and enhancing the leaving ability of the halide... 

Earlier conclusions which were necessarily based on the assumption that AS is independent of the temperature therefore sometimes require revision. For example, the suggestion that a-substitution in alkyl halides increases AS for S 1 solvolysis by enhancing steric hindrance to... 

Nucleophilic Substitution in Alkyl Halides — S l vs S 2 Comparison Table 20-1... 

Substitution and Addition Reactions. All types of reactions between inorganic anions and organic partners can be executed under the PTC conditions. Nucleophilic aliphatic substitution in alkyl halides with cyanide anions to form nitriles was presented in the Introduction as a typical example of PTC on which the basic principles and characteristic features of this catalysis were discussed. 

This mechanism tends to be observed for 18e carbonyls. The alternative, initial attack of a phosphine, would generate a 20e species. While it is not forbidden to have a 20e transition state (after all, NiCp2 is a stable 20e species), the 16e intermediate of Eq. 4.28 provides a lower-energy path in many cases. This is reminiscent of the SnI mechanism of substitution in alkyl halides. The activation enthalpy required for the reaction is normally close to the M—CO bond strength, because this bond is largely broken in going to the transition state. A5 is usually positive and in the range 10-15 eu (entropy units), as expected for a dissociative process in which the transition state is less ordered. 

In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution when the ring bears an 0- or p-nitro group. The reaction of l-fluoro-2,4-dinitrobenzene, known as Sanger s reagent, with amino acids takes place readily at room temperature and is the basis of a method used in protein structure determination. 

Nitriles contain the —C=N functional group. We have already discussed the two main procedures by which they are prepared, namely, the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins. Table 20.6 reviews aspects of these reactions. Neither of the reactions in Table 20.6 is suitable for aryl nitriles (ArC N) these compounds are readily prepared by a reaction to be discussed in Chapter 22. 

Alkyl azides, prepared by nucleophilic substitution of alkyl halides by sodium azide, as shown in the first entry of Table 22.3, are reduced to alkylamines by a variety of reagents, including lithium aluminum hydride. 

Aryl halides can also be reduced by tin hydrides76,77, although these reactions always require initiators because the stronger C—X bonds in aryl halides are less reactive than the C—X bonds in alkyl halides. In fact, a series of meta- and para-substituted bromobenzenes, where X is either meta- or para-CH3O-, C=N, Cl, F, CF3, CH3, Bu-f or 2,6-dichloro, have been reduced by tributyltin deuteride (equation 60). It is worth noting that the more reactive bromide is reduced selectively in the presence of the less reactive chloride and fluoride groups (equation 61). 

Two methods are used for the SPPS of peptoids and peptoid-peptide hybrids (Scheme 41). The first method 122,215 (Scheme 41, route A) called the premade monomer method involves the preparation of a Fmoc-protected monomer in solution (see Section 10.1.1.4.1 and Table 8) and its incorporation into the peptoid or the peptoid-peptide hybrid using Fmoc/SPPS. The second method1216217 (Scheme 41, route B) called the submonomer method involves the formation of the peptoid monomer on the solid support by first forming a bromoacetylated peptide-resin and then substituting the alkyl halide with the appropriate alkyl- or side-chain protected co-functionalized alkylamine. 

Enolate ions, which are usually strong nucleophiles, are more important in preparative applications than are the enols. In additions to carbonyl groups, the carbon end, rather than the oxygen end, attacks but in SA,2 substitutions on alkyl halides, significant amounts of O-alkylation occur. The more acidic compounds, such as those with the j3-dicarbonyl structure, yield enolates with the greater tendency toward O-alkylation. Protic solvents and small cations favor C-alkylation, because the harder oxygen base of the enolate coordinates more strongly than does the carbon with these hard Lewis acids.147... 

Aryl halides are relatively unreactive toward nucleophilic substitution reactions. This lack of reactivity is due to several factors. Steric hindrance caused by the benzene ring of the aryl halide prevents SN2 reactions. Likewise, phenyl cations are unstable, thus making SN1 reactions impossible. In addition, the carbon-halogen bond is shorter and therefore stronger in aryl halides than in alkyl halides. The carbon-halogen bond is shortened in aryl halides for two reasons. First, the carbon atom in aryl halides is sp2 hybridized instead of sp3 hybridized as in alkyl halides. Second, the carbon-halogen bond has partial double bond characteristics because of resonance. 

A similar strategy in aqueous media has now been applied to the nucleophilic substitution of alkyl halides or tosylates using readily available alkali azides, thiocyanates or sulfinates under microwave irradiation. The approach afforded safe and efficient preparation of azides, thiocyanates and sulfones (Scheme 23) (Ju et al., personal communications). 

SN1 versus S There are two different mechanisms involved in the nucleophilic substitution of alkyl halides. When polar aprotic solvents are used, the SN2 mechanism is preferred. Primary alkyl halides react more quickly than secondary alkyl halides, with tertiary alkyl halides hardly reacting at all. Under protic solvent conditions with non-basic nucleophiles (e.g. dissolving the alkyl halide in water or alcohol), the SN1 mechanism is preferred and the order of reactivity is reversed. Tertiary alkyl halides are more reactive than secondary alkyl halides and primary alkyl halides do not react at all. 

Azaphosphoranium salts 39 have been used as phase-transfer catalysts for the Finkelstein and Kolbe reactions (substitution of halogen in alkyl halides by iodide and cyanide, respectively) (78PS145). Representatives of... 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

In the presence of sodamide the anionic form of 2-amino-l-ethylbenzimidazole is substituted by alkyl halides on both the annular and exocyclic nitrogens. With butyl and isopropyl iodides the proportion of dialkylated product is increased. The synthetic utility of such nucleophilic reactions of 2-aminobenzimidazole is exemplified by reactions with ethyl cyanoacetate, acetoacetic ester and ethyl benzoylacetate, when subsequent cyclization of the initial products also gives pyrimidobenzimidazole derivatives (Scheme 117). 

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