Primary substrates, elimination reactions

Effect of Solvent on Elimination versus Substitution. Increasing polarity of solvent favors Sn2 reactions at the expense of E2. In the classical example, alcoholic KOH is used to effect elimination, while the more polar aqueous KOH is used for substitution. Charge-dispersal discussions, similar to those on page 450, only partially explain this. In most solvents, SnI reactions are favored over El. The El reactions compete best in polar solvents that are poor nucleophiles, especially dipolar aprotic solvents" A study made in the gas phase, where there is no solvent, has shown that when 1-bromopropane reacts with MeO only elimination takes place no substitution even with this primary substrate." ... 

Now let s consider the effect of the substrate on the rate of an E2 process. Recall from the previous chapter that Sn2 reactions generally do not occur with tertiary substrates, because of steric considerations. But E2 reactions are different than Sn2 reactions, and in fact, tertiary substrates often undergo E2 reactions quite rapidly. To explain why tertiary substrates will undergo E2 but not Sn2 reactions, we must recognize that the key difference between substitution and elimination is the role played by the reagent. In a substitution reaction, the reagent functions as a nucleophile and attacks an electrophilic position. In an elimination reaction, the reagent functions as a base and removes a proton, which is easily achieved even with a tertiary substrate. In fact, tertiary substrates react even more rapidly than primary substrates. 

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). 

Step 1 is fundamentally an SN2 reaction (kinetics related to structural variations of the reactants,16 8 retention of stereochemistry at phosphorus912), except in those instances wherein a particularly stable carbocation is produced from the haloalkane component.13 A critical experiment concerned with verification of the Sn2 character of Step 1 by inversion of configuration at the carbon from which the leaving group is displaced was inconclusive because elimination rather than substitution occurred with the chiral secondary haloalkane used.14 An alternative experiment suggested by us in our prior review using a chiral primary substrate apparently has not yet been performed.2... 

Another polarimetric method for the accurate determination of KIEs bears a strong resemblance to the isotopic quasi-racemate method, described above. In this method, Bach and co-workers (1991) utilized what they called isotopically engendered chirality to determine the primary deuterium KIE for an elimination reaction. In theory, the method can be used for any reaction where a substrate with a plane of symmetry yields, under normal conditions, a racemic mixture. For instance, if the plane of symmetry in the unlabelled... 

Solvolysis of (29-X, X = I, Br, OBs) in 25vol.% acetonitrile in water gives elimination product (32) and substitution products (33a) and (33b).17 The rate of elimination increases with increasing acidity of the substrate (Bronsted a > 0) as evidenced by results for ring-substituted substrates (30-X) and (31-X). However, for elimination reactions of the brosylates (29-OBs) and (31-OBs), the small kinetic deuterium isotope effect (kH/kD = 2.0 0.1 and 2.8 0.1, respectively) is believed to be a consequence of competing El reaction via a primary ion pair. 

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. 

A small amount (up to one equivalent) of HMPT is necessary in order to accelerate the alkylation step. Sec.-butyl bromide gives 38 % of the expected ynamine together with 25 % butene and 22 % of diethylaminoacetylene. Expectedly, t-butyl bromide undergoes only elimination and it serves as a convenient proton source to liberate N-ethynyl-methylaniline 106 Primary substrates react smoothly, however, even in complex cases and with this in mind, the scope of this reaction is almost unlimited. One more example illustrates this technique (83),35). 

However, even with primary substrates byproduct formation via elimination and substitution by the solvent (e.g., ethylene glycol or methanol) is a common side reaction. For example, treatment of 1,2 3.5-di-0-methylene-6-0-tosyl-a-D-glucofuranose (5) with anhydrous potassium fluoride in boiling ethylene glycol for three minutes gives a mixture of 6, 7 and... 

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... 

RSSF spectroscopy has also been used to study the effect of active site mutations on the 3-elimination reaction catalyzed by tryptophanase. In many PLP-de-pendent enzymes, the Lys residue that forms the E(Ain) with the cofactor is preceded by a basic residue in the primary amino acid sequence. Phillips et al. (106) have examined the effect of changing Lys 269 to Arg on the formation and accumulation of reaction intermediates. The activity of the mutant enzyme is only 1096 of the native enzyme. Secondly, the mutant enzyme exhibits an altered pH dependence both in the spectrum of the native enzyme and in the catalytic rate profile. RSSF studies of the reaction of/.-alanine, z-Trp, S-methyl-z-cysteine, S-benzyl-z-cysteine (SBC), and oxindolyl-/-alanine show that all these various substrates react with the enzyme to form covalent intermediates. However, the rate and extent of quinonoid accumulation is greatly reduced. Analysis of quinonoid bands formed in the reactions of SBC and oxindolyl-z-alanine with tryptophanase show that mutation effects the equilibrium distribution of intermediates, but does not perturb either the band shape or the A x of the observed quinonoid intermediates. Therefore, the structure of the quinonoid intermediate and the surrounding active site environment are similar to the wild-type enzyme. SWSF characterization of these reactions show that the Keq for E(Aex) formation with each substrate is similar to that found for the wild-type enzyme. Instead, the primary effect of the Lys 269 Arg mutation is at the catalytic step in which the a-proton is removed from E(Aex) to form a quinonoid. These studies show that Lys 269 is not a critical catalytic residue nevertheless it does contribute to the conformational and/or electrostatic environment of the active site that is necessary for the formation and breakdown of quinonoidal species. 

A number of enzymes use iminium ion formation not only to activate the substrate carbonyl group for a-proton abstraction, but also to enhance the rate of elimination of a group from the iminium thus formed. In Section 2 above, an elimination reaction similar to that shown in Scheme 18 was used as an example of primary amine catalyzed a-proton abstraction, and the data was also unambiguous since the... 

Borohydride as the nucleophile, to afford the corresponding alkanes only highly congested substrates experience competing attack at nitrogen4 Similarly, primary aliphatic amines, when ditosylated and treated with iodide ion in DMF at 90-120 °C yielded, as their major products, the corresponding alkyl iodides, with some competition arising from elimination reactions (eqs 33 and 34)4 ... 

Nucleophilic anions, i.e. halides, pseudohalides, alkoxides, phenoxides, and thio-phenoxides, are particularly suitable for these reactions. Even anions of lower reactivity in nucleophilic displacements, i.e. carboxylates, nitrates, nitrites and hydroperoxides, find practical application under PTC conditions. Reactions are rigorously Sf,2 in mechanism primary substrates are thus most suitable, since secondary substrates afford elimination products in high yields, especially when reacted at high temperatures, and tertiary substrates only give rise to elimination. This behaviour is consistent with the low polarity of the organic phase, preventing unimolecular mechanisms and favouring elimination over substitution when the reaction center is not a primary carbon atom. 

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