Elimination strongly basic nucleophiles

Next, we examine the two reactions to determine whether both are expected to give a good yield of the target compound. Because route A combines a strongly basic nucleophile and a secondary alkyl halide, we expect the major product to result from elimination by the E2 mechanism. Route B, on the other hand, employs a primary alkyl halide that cannot give elimination (it has no hydrogen on the /3-carbon) and that is an excellent substrate for an SN2 substitution because it is benzylic. Route B is the obvious choice. 

The target is now cyclopentanol. Alcohols can be prepared from alkyl halides by reaction with hydroxide ion as the nucleophile. Again, however, the combination of a strongly basic nucleophile and a secondary alkyl halide will result in an unacceptable amount of elimination. A better plan is to treat bromocyclopentane with acetate ion in an aprotic solvent such as DM SO. followed by cleavage of the ester to cyclopentanol ... 

Strongly basic nucleophiles such as an amide ion allowed a nucleophilic substitution via an elimination-addition mechanism of cyclopropane derivatives possessing an acidic hydrogen atom " ". Aminocyclopropanes 121 and 122 were synthesized in this manner from the corresponding halogenocyclopropanes " (equations 28 and 29). 

Strongly basic nucleophiles irreversibly deprotonate carboxylic acids, forming carboxylate anions. Addition-elimination reactions on carboxylate anions are hard to do because (1) the addition is hard to do and (2)... 

The binding of the nucleophile to the boron atom in structure 5 facilitates the internal migration and nucleophilic displacement with inversion to the point that side reactions such as P-elimination are not observed. Strongly basic nucleophiles work best in the conversion of 4 into 7, but the displacement process is assisted by the boron atom even if a fiilly covalent bond to boron is probably not involved [9j. 

Acyl chlorides and esters undergo a nucleophilic addition-elimination reaction with strongly basic nucleophiles (R" and H") to form a ketone or an aldehyde, which then undergoes a nucleophilic addition reaction with a second equivalent of the nucleophile. Electronic and steric factors cause an aldehyde to be more reactive than a ketone toward nucleophilic addition. 

Strongly basic nucleophiles give more elimination as steric bulk increases... 

Reactions of simple primary haUdes with strongly basic nucleophiles give mostly Sn2 products. As steric bulk is increased around the carbon bearing the leaving group, substitution is retarded relative to elimination because an attack at carbon is subject to more steric hindrance than is an attack on hydrogen. Thus, branched primary substrates give about equal amounts of Sn2 and E2 reaction, whereas E2 is the major outcome with secondary substrates. 

However, if sodium ethoxide, a strongly basic nucleophile, is added to the ethanol, an E2 reaction competes with the substitution reaction. The amount of elimination product is increased to a total of about 93% of the product mixture. Only 7% of the ether product is formed. Most of the elimination product is derived from the E2 reaction. 

Nucleophilic substitution can be employed to introduce fluorine into specific positions within an aromatic ring, and the Halex (halogen exchange) reaction is commonly used in industty. ° Unlike aliphatic reactions, elimination is usually not an issue for aromatic substrates, and as such, strongly basic nucleophilic sources of fluoride can be utilised in the reaction. The reaction works for electron deficient aromatics and is generally carried out... 

The Claisen condensation is initiated by deprotonation of an ester molecule by sodium ethanolate to give a carbanion that is stabilized, mostly by resonance, as an enolate. This carbanion makes a nucleophilic attack at the partially positively charged carbon atom of the e.ster group, leading to the formation of a C-C bond and the elimination ofan ethanolate ion, This Claisen condensation only proceeds in strongly basic conditions with a pH of about 14. 

As a practical matter, elimination can always be made to occur quantitatively. Strong bases, especially bulky ones such as terr-butoxide ion, react even with primary alkyl halides by an E2 process at elevated temperatures. The more difficult task is to find conditions that promote substitution. In general, the best approach is to choose conditions that favor the Sn2 mechanism—an unhindered substrate, a good nucleophile that is not strongly basic, and the lowest practical temperature consistent with reasonable reaction rates. 

Secondary alkyl halides Sjvj2 substitution occurs if a weakly basic nucleophile is used in a polar aprotic solvent, E2 elimination predominates if a strong base is used, and ElcB elimination takes place if the leaving group is two carbons away from a carbonyl group. Secondary allylic and benzyiic alkyl halides can also undergo S l and El reactions if a weakly basic nucleophile is used in a pro tic solvent. 

Nucleophilic substitution reactions of halide anions in aprotic solvents are often accompanied by elimination reactions. For instance, reactions of secondary alkyl halides with potassium fluoride solubilized in acetonitrile with the aid of 18-crown-6 [3] give olefins as the main reaction product (Liotta and Harris, 1974). Similarly, the dicyclohexyl-18-crown-6 complex of potassium iodide acted exclusively as a base in its reaction with 2-bromo-octane in DMF (Sam and Simmons, 1974). The strongly basic character of weakly solvated fluoride has been exploited in peptide synthesis (Klausner and Chorev, 1977 Chorev and Klausner, 1976). It was shown that potassium fluoride solubilized... 

Secondary alkyl halides may undergo substitution or elimination under basic conditions, but with the strong hindered base and lousy nucleophile LDA, elimination is certain to occur. The product is CH3CH=CH2. 

Exps. 9 and 10 are convincing illustrations of the high lrineiic acidity of the ethynyl proton. In principle, there are four reaction pathways if l-bromo-5-hexyne and a strongly basic reagent are allowed to interact abstraction of the acetylenic proton, Br-metal exchange, displacement of Br by the "nucleophilic" part of the base, and elimination of HBr with formation of HCsC(CH2)2CH=CH2- Only the first process takes place under the conditions of this experiment. The kinetic stability of the intermediate LiOC(CH2)4Br is sufficient to allow for successful functionalizations with a number of reagents. For alkylations with most of the alkyl halides, the polarity of the medium will usually be insufficient. 

As with the strongly basic NH, [Problem 20.25(a), nucleophilic attack by OH at C , followed by H -elimination, yields an enolic intermediate that tautomerizes to 2-pyridone. 

Fluorine in 4-fluorophenyl ketones, as well as in 2,4-difluorophenyl ketones and in 2,4-difluoro-benzaldehydc, can readily be eliminated by sulfur nucleophiles under strongly basic conditions in polar solvents. With different substituents bonded to the carbonyl group a variety of products 4 can be obtained. 

A tertiary alkyl halide when treated with sodium methoxide forms an ether or an alkene (Above fig.). A protic solvent is used here and this favours both the SN1 and El mechanisms. However, a strong base is also being used and this favours the E2 mechanism. Therefore, the alkene would be expected to be the major product with only a very small amount of substitution product arising from the SN2 reaction. Heating the same alkyl halide in methanol alone means that the reaction is being done in a protic solvent with a non-basic nucleophile (MeOH). These conditions would yield a mixture of substitution and elimination products arising from the SN1 and El mechanism. The substitution product would be favoured over the elimination product. 

The enolate ions of esters or ketones can also be alkylated with alkyl halides to create larger carbon skeletons [Following fig.(b)]. The most successful nucleophilic substitutions are with primary alkyl halides. With secondary and tertiary alkyl halides, the elimination reaction may compete, particularly when the nucleophile is a strong base. The substitution of tertiary alkyl halides is best done in a protic solvent with weakly basic nucleophiles. However, yields may be poor. 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

Increasing branching favours elimination over substitution and strongly basic hindered nucleophiles always eliminate unless there is no option... 

Hydrogen attached to ring carbon atoms of neutral azines, and especially azinium cations, is acidic and can be replaced by a metal formally being removed as a proton. Alkyllithiums can be used as bases for this purpose however, the reaction can be accompanied by addition of the alkyl anion to the ring C=N bond. To avoid this, sterically hindered bases with strong basicity but low nucleophilicity can be utilized. Among these are lithium tetramethylpiperidide (LiTMP) and lithium diisopropylamide (LDA). If the anion contains an ortho halogen atom, then this can be eliminated to form a pyridyne (see Section 3.2.3.10.1). 

Carbenium ions react with neutral nucleophiles to produce onium ions. A favorable equilibrium between active carbenium ions and temporarily inactive onium ions can be used to produce well-defined polymers (Chapter 4). However, rather than reacting directly with carbenium ions, nucleophiles may also react with Lewis acids to form strong complexes, thereby reducing their activity and ability to ionize covalent compounds. A third reaction that basic nucleophiles may be involved in is /3-proton elimination this transfer reaction may subsequently result in termination if it involves a strong base [Eq. (131)]. 

Nucleophiles (or electron donors) may react with cationic species in three different ways (see Section VI.B.2 see also Table 2, Section V.A.2 for examples). They can reversibly form onium ions, complexes and covalent species, and if they are basic enough, they may eliminate /3-protons [cf., Chapter 3, Eq. (131)]. In the first reaction, nucleophiles are used to control the polymerization rate because onium ions are inactive dormant species. They can be added at concentrations higher than salts, and can considerably reduce the lifetimes of both unpaired cations and ion pairs by converting them into dormant onium species. In the second reaction, nucleophiles can also affect the polymerization rates by coordination to Lewis acids and reducing their strength. Both reactions are beneficial for controlled polymerization. The third reaction, favored by strongly basic species, should be avoided. 

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