1-Bromobutane nucleophilic substitution

In the first systematic study on nucleophilic substitutions of chiral halides by Group IV metal anions, Jensen and Davis showed that (S )-2-bromobutane is converted to the (R)-2-triphenylmetal product with predominant inversion at the carbon center (Table 5)37. Replacement of the phenyl substituents by alkyl groups was possible through sequential brominolysis and reaction of the derived stannyl bromides with a Grignard reagent (equation 16). Subsequently, Pereyre and coworkers employed the foregoing Grignard sequence to prepare several trialkyl(s-butyl)stannanes (equation 17)38. They also developed an alternative synthesis of more hindered trialkyl derivatives (equation 18). 

The mechanism of nucleophilic substitution in primary halogenoalkanes proceeds as follows, using 1-bromobutane as an example ... 

The catalytic activity of cross-linked polymeric sulfoxides differing in the functionality of the polystyrene matrix (the general formula is ( -(CH20CH2) -R, whereby (P) is the polystyrene matrix cross-linked by divinylbenzene, R = H or CH3, and n = 1, 2 or 3), has been studied in nucleophilic substitution reactions between alkyl bromides (1-bromobutane and 1-bromooctane) and phenoxides, iodides, thiocyanates or cyanides of alkaline metals under the conditions of catalytic three-phase reactions in the liquid-solid-liquid system [66]. The reaction is carried out in a toluene-water medium between 70-100°C. In the systems the rate of anion transfer from the liquid phase to the organic phase decreases in the sequence PhO > J > SCN > CN . 

Chapter6 Alkyl Halides Nucleophilic Substitution and Elimination EXAMPLE Reaction of 1-bromobutane with sodium methoxide gives 1-methoxybutane. 

Equation 8.28 shows only the anionic nucleophile explicitly, since the counterion does not appear to take part in the reaction. Nevertheless, the counterion affects the solubility of a nucleophilic salt, which therefore can influence the polarity of the solvent needed for the reaction. An alternative to the use of a more polar solvent to dissolve a salt for nucleophilic substitution is to use crown ether additives. Crown ethers are cyclic polyethers that can coordinate with cations and therefore increase their solubility in organic solvents. The nomenclature provides the total number of atoms and the number of oxygen atoms in the ring. Compoimd 51 is 12-crown-4, and 52 is 18-crown-6 (Figure 8.32). Coordination of a crown ether with a cation helps to dissolve the salt in a less polar solvent and leaves the anion relatively unsolvated. The activation energy for substitution therefore does not include a large term for desolvation of the nucleophilic anion, and the reactions are fast. For example, adding dicyclohexano-18-crown-6 (53) to a solution of 1-bromobutane in dioxane was found to increase its reactivity with potassium phenoxide by a factor of 1.5 x 10. Moreover, Liotta and Harris were able to use KF solubilized with 18-crown-6 (52) to carry out Sn2 reactions on 1-bromooctane in benzene. ... 

As we have already seen, an acetylide anion is a strong base. An acetylide anion is also a nucleophile it has an unshared pair of electrons that it can donate to another atom to form a new covalent bond. In this instance, an acetylide anion donates its unshared pair of electrons to the carbon of a methyl or primary haloalkane, and in so doing, the acetylide nucleophile replaces the halogen atom. This type of reaction is called a nucleophilic substitution. For example, treating sodium acetylide with 1-bromobutane gives 1-hexyne. 

Now, let s draw out the forward scheme. Acetylene is reduced to ethylene using H2 and Lindlar s catalyst. HBr addition, followed by Sn2 substitution with an acetylide nucleophile (made by deprotonation of acetylene with sodium amide) gives 1-butyne. Reduction to 1-butene with H2 and Lindlar s catalyst followed by anrt-Markovnikov addition of HBr in the presence of peroxide produces 1-bromobutane. A substitution reaction with sodium acetylide gives 1-... 

Now we need to make the alkyne needed in the above hydrogenation. The starting material provided lacks the butyl group at the triple bond. To attach the alkyl group, we can perform a nucleophilic substitution at 1-bromobutane with the acetylide ion generated from the starting material, by using sodium amide ... 

Rate of substitution by sulfur nucleophile deemed negligible (see Table VIII). gRate of dehydrohalogenation by H20 deemed negligible (78). hkH2o,SN for hydrolysis of 2-bromobutane used as a surrogate. 

In the process illustrated in Figure 10.1, acetate ion is termed a synthetic equivalent of hydroxide ion because the final product is the same as if hydroxide ion were used directly. But the two-step process results in a higher yield of 2-butanol than could be obtained by a direct substitution reaction of 2-bromobutane with hydroxide ion. The use of a carbonyl group to decrease the basicity or nucleophilicity of a reagent in order to... 

In both cases, the bromide ion is the leaving group and is attached to a primary carbon atom. In the case of bromobutane, the carbon chain is off to one side and does not interfere with the approach of the nucleophile. However, in contrast, in the case of neo-pentylbromide, there is the large /-butyl group that obstructs the approach of the incoming nucleophile. This steric hindrance decreases the rate of SN2 substitution. 

Our electron sink also presents two alternative routes, substitution or elimination. With a p abH of 10.7 and a soft carbon anion, this is a good nucleophile and a moderate base. Our 1-bromobutane presents a primary unhindered site so the decision is clearly in the substitution quadrant (Section 9.5). There are two possible substitutions, SnI ... 

In contrast to the Sn2 reaction, the SnI reaction of (S)-2-bromobutane forms two substitution products—one with the same relative configuration as the reactant and the other with the inverted configuration. In an SnI reaction, the leaving group leaves before the nucleophile attacks. This means that the nucleophile is free to attack either side of the planar carbocation. If it attacks the side from which the bromide ion left, the product will have the same relative configuration as the reactant. If it attacks the opposite side, the product will have the inverted configuration. 

Aprotic solvents, on the other hand, lack —OH groups and do not solvate anions very strongly, leaving the anions much more able to express their nucleophilic character. Table 8.7 compares the second-order rate constants k for 8 2 substitution of 1-bromobutane by azide ion (a good nucleophile) in several polar aprotic solvents with the corresponding fc s for the much slower reactions in polar protic solvents. 

When 2-methyl-2-propanol tert-hvXyl alcohol, 65) is treated with concentrated HCl, 2-chloro-2-methylpropane (2-chloro-2-methylpropane ter -butyl chloride, 93) is isolated in 90% yield. Similarly, when 1-butanol (94) is treated with 48% HBr in the presence of sulfuric acid, a 95% yield of 1-bromobutane (96) is obtained. In both reactions, the oxygen of the alcohol reacts as a Br0nsted-Lowry base in the presence of the protonic acids, HCl, or sulfuric acid. The fact that alkyl halides are produced clearly indicates that these are substitution reactions. In previous sections, tertiary halides gave substitution reactions when a nucleophilic halide ion reacted by an Sfjl mechanism that involved ionization to a carbocation prior to reaction with the halide. Primary halides react with a nucleophilic halide ion by an 8 2 mechanism. It is reasonable to assume that tertiary alcohols and primary alcohols will react similarly, i/the OH unit is converted to a leaving group. 

This model for the transition state is based on experimental evidence. When (f )-2-bromobutane reacts with sodium hydroxide, the substitution product is (5)-2-butanol. The reaction therefore occurs with inversion of configuration. This result indicates that the nucleophile approaches the electrophilic carbon atom from the back side—that is, from the side direcdy opposite the leaving group. The leaving group departs simultaneously from the opposite side of the substrate. 

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