Secondary substrates, elimination reactions

To sum up, primary and secondary substrates generally react by the Sn2 mechanism and tertiary by the SnI mechanism. However, tertiary substrates seldom undergo nucleophilic substitution at all. Elimination is always a possible side reaction of nucleophilic substitutions (wherever a P hydrogen is present), and with tertiary substrates it usually predominates. With a few exceptions, nucleophilic substitutions at a tertiary carbon have little or no preparative value. However, tertiary substrates that can react by the SET mechanism (e.g., /i-N02C6H4CMe2Cl) give very good yields of substitution products when treated with a variety of nucleophiles. ... 

When the reageht fuhotiohs exclusively as a nucleophile (ahd hot as a base), ohiy substitutioh reactions occur (not elimination). The substrate determines which mechahism operates. 3 2 predominates for primary substrates, and 3 1 predominates for tertiary substrates. For secondary substrates, both 3 2 ahd 3 1 cah occur, although 3 2 is generally favored (especially when a polar aprotic solvent is used). 

Saunders and co-workers (Amin et al., 1990) used E2 elimination reactions in the p-substituted 2-phenylethyl system to test the new criteria for tunnelling suggested by the above calculations. The actual substrates and base/solvent systems they used were (2-phenylethyl-2-f)-trimethylammonium bromide, [19], with sodium ethoxide in ethanol, 2-phenylethyl-2-f bromide, [20], with potassium t-butoxide in t-butyl alcohol and 2-(p-chlorophenyl)ethyl-2-f tosylate, [21], with potassium t-butoxide in t-butyl alcohol. When equation (57) was applied to the experimental secondary (kB/ S) KIEs in Table 39, the calculated /th h KIEs were 1.106 0.033 and 1.092 0.026 for [19] and [21],... 

L is the hydrogen or deuterium atom that is not transferred in the elimination reaction and T is tritium that is present in tracer quantities. These substrates were chosen so that the reactions would have transition states ranging from very ElcB-like for [22], to central or intermediate for [23], to El-like for [24]. For practical reasons, the base/solvent system could not be kept constant as was originally intended. EtO /EtOH was used in the reaction with substrates [22] and [23] whereas Bu,0"/But0H was used with substrate [24]. Although the secondary tritium KIE (when L = H) for the reaction of [22] was... 

Both of these mechanisms involve rate-determining formation of a carbocation, so they most commonly occur with tertiary (best) or secondary substrates in polar solvents. The reaction conditions are often neutral or acidic to avoid the presence of any strong base or strong nucleophile that might favor the SN2 or E2 pathways. Because the step that controls which product is formed occurs after the rate-determining step, it is much more difficult to influence the ratio of substitution to elimination here. In general, some elimination always accompanies an SN1 reaction and must be tolerated. An example is provided in the equation in Figure 9.7. 

When an alkoxide ion is used as the nucleophile, the reaction is called a Williamson ether synthesis. Because the basicity of an alkoxide ion is comparable to that of hydroxide ion, much of the discussion about the use of hydroxide as a nucleophile also applies here. Thus, alkoxide ions react by the SN2 mechanism and are subject to the usual Sn2 limitations. They give good yields with primary alkyl halides and sulfonate esters but are usually not used with secondary and tertiary substrates because elimination reactions predominate. 

Cyanide ion reacts by the SN2 mechanism and aprotic solvents are often employed to increase its reactivity. Yields of substitution products are excellent when the leaving group is attached to a primary carbon. Because of competing elimination reactions, yields are lower, but still acceptable, for secondary substrates. As expected for an SN2 process, the reaction does not work with tertiary substrates. Substitution with cyanide ion adds one carbon to the compound while also providing a new functional group for additional synthetic manipulation. Some examples are given in the following equations ... 

Sulfur occurs directly beneath oxygen in the periodic table. Therefore, sulfur compounds are weaker bases but better nucleophiles than the corresponding oxygen compounds. Sulfur compounds are excellent nucleophiles in SN2 reactions, and because they are relatively weak bases, elimination reactions are not usually a problem. Yields are good with primary and secondary substrates. For similar reasons, phosphorus compounds also give good yields when treated with primary and secondary substrates in Sn2 reactions. The following equations provide examples of the use of these nucleophiles ... 

Elimination reactions are a useful method for the preparation of alkenes, provided that certain limitations are recognized. One problem is the competition between substitution and elimination. The majority of eliminations are done under conditions that favor the E2 mechanism. In these cases, steric hindrance can be used to slow the competing SN2 pathway. Tertiary substrates and most secondary substrates give good yields of the elimination product when treated with strong bases. Sterically hindered bases can be employed with primary substrates to minimize substitution. 

In general, secondary and tertiary alcohols do not give satisfying results in fluorination reactions with sulfur tetrafluoride when elimination reactions are possible they become an important side reaction, e.g, with secondary substrates such as l,1.1.4,4,4-hexafluorobutan-2-ol (2). ... 

Yields (isolated) are about 80 % in the case of primary aliphatic halides and tosylates. Yields are less satisfactory in the case of secondary substrates owing to olefin-forming elimination reactions, which can be minimized by use of TIIF as solvent. Primary... 

Sodium sulfhydride (NaSH) is a much better reagent for the formation of thiols (mercaptans) from alkyl halides than H2S and is used much more often. It is easily prepared by bubbling H2S into an alkaline solution, but hydrosulfide on a supported polymer resin has also been used. " The reaction is most useful for primary halides. Secondary substrates give much lower yields, and the reaction fails completely for tertiary halides because elimination predominates. Sulfuric and sulfonic esters can be used instead of halides. Thioethers (RSR) are often side products. The conversion can also be accomplished under neutral conditions by treatment of a primary halide with F and a tin sulfide, such as PhsSnSSnPhs. An indirect method for the preparation of a thiol is the reaction of an alkyl halide with thiourea to give an isothiuronium salt (119), and subsequent treatment with alkali or a... 

Reaction of an alkyl halide or tosylate with a nucleophile/base results either in substitution or in elimination. Nucleophilic substitutions are of two types Sn2 reactions and S l reactions. In the Sn2 reaction, the entering nucleophile attacks the halide from a direction 180° away from the leaving group, resulting in an umbrella-like Walden inversion of configuration at the carbon atom. The reaction shows second-order kinetics and is strongly inhibited by increasing steric bulk of the reactants. Thus, Sn2 reactions are favored for primary and secondary substrates. 

The proposed elimination (El cb) mechanisms (mechanisms A and B) were the result of studies of the behavior of substrate analogs and secondary deuterium isotope effects in the PAL reaction,solvent isotope exchange studies with HAL, ° and kinetic isotope effects studies of a ring perdeuterated phenylalanine in PAL. Later, a synthetic model putatively mimicking the PAL elimination reaction (mechanism B) was also described (Figure 15), taking into consideration the electrophilic behavior of a Michael acceptor within a sterically appropriate distance from a Phe (l)-like substrate. Upon treatment with a Lewis acid (AICI3) and... 

For secondary halides in aqueous solvents, unimolecular and bimolecular processes compete, and the result is usually a mixture of products. With strong bases and protic solvents other than water, bimolecular elimination is usually faster than substitution, although this is only an assumption and accurate predictions can be difficult with secondary substrates. In polar aprotic solvents, bimolecular processes are usually faster. If a strong base is present and a protic solvent is used, bimolecular elimination is usually preferred to bimolecular substitution, but this is another assumption. If ethanol is used as a solvent and sodium ethoxide is a nucleophilic base. Table 2.9 shows the competition between bimolecular substitution (Sn2) and bimolecular elimination (E2) for a series of alkyl bromides. The preference for E2 reactions of secondary and tertiary halides in this protic solvent is clearly shown. 

B.ii. The SnI Reaction. The mechanistic rationale described above results from many years of experimental observations about the SnI reaction (statements 1-6 below). 25 i i general, the SnI process occurs in those cases where water is present as a solvent or co-solvent, there is a good leaving group and the substrate is tertiary or secondary. A SnI reaction can occur in any polar protic solvent such as methanol, ethanol, or acetic acid, but ionization is much slower in these solvents relative to water because they are not as efficient for, the separation of ions (sec. 2.7.B). If ionization is relatively slow, faster reactions (Sn2 or elimination processes) often predominate. It is convenient to assume that SnI reactions occur only in aqueous media and use this assumption to predict product distributions for a given set of reaction conditions. As with any... 

---