1 Substitution and Elimination Reactions. 7.1. Definitions. In an acid–base reaction such as CH3CO2H + NH3 → CH3CO2– + NH4+, the N acts as a nucleophile (Greek for “loving the nucleus), the H acts as an electrophile (“loves electrons”), and the O that accepts the pair of electrons acts as a leaving group. The acid–base reaction is the simplest model for a substitution reaction, which is a reaction in which a σ bond between atom 1 and atom 2 is replaced by a σ bond between atom 1 and atom 3. Substitution reactions are incredibly important in organic chemistry, and the most important of these involve substitutions at C. For example: This substitution reaction, discovered in 1849, involves the nucleophilic O making a new bond to the electrophilic C, and the bond between the electrophilic C and the leaving group I breaking. Any Brønsted base can also act as a nucleophile, and any nucleophile can also act as a Brønsted base, but some compounds are particularly good bases and particularly poor nucleophiles, whereas some are particularly poor bases and particularly good nucleophiles. Any Brønsted or Lewis acid can also act as an electrophile, but there are many electrophiles that are neither Brønsted nor Lewis acids (as in the example above). A haloalkane, e.g. CH3CH2Br, can in principle undergo either of two polar reactions when it encounters a lone pair nucleophile, e.g. MeO–. First, MeO– might replace Br– at the electrophilic C atom, forming a new C–O bond and giving an ether as the product. This is substitution, because the C–Br σ bond is replaced with a C–O σ bond. Second, MeO– might attack a H atom that is adjacent to the electrophilic C atom, giving MeOH, Br–, and an alkene as products. The electrons in the C–H bond move to form the π bond, and the electrons in the C–X bond leave with X–. This is elimination, because a new π bond is formed, and because the elements of the organic starting material are now divided between more than one product. Elimination requires that the substrate have a C–X bond and adjacent C–H bonds, while substitution requires only that the substrate have a C–X bond.2 A reaction involves the formation and cleavage of bonds. A mechanism is a story we tell about the changes in the arrangment of the electrons in the starting materials that led to products. When multiple bonds are made or broken, they are usually not made and broken all at one time. A mechanism describes the order in which the different bonds are made and broken and which electrons moved to break and form particular bonds. A mechanism can also help us generate hypotheses about the rate and stereochemical results of a reaction that we can then use to test whether our idea about how the reaction occurred is correct. We will see soon that there are two mechanisms by which nucleophilic substitution can occur, and there are two mechanisms by which elimination can occur. The purpose of this chapter is to learn how the reaction conditions and the structures of the Lewis base and the substrate affect the relative rates of the different possible reaction pathways. Substitution and elimination reactions can occur under either basic or acidic conditions. The reactions have very different characteristics under basic or acidic conditions, so we'll discuss them separately. 7.2. Leaving Groups. All substitution and elimination reactions require a σ bond electrophile. The most common such electrophile is a haloalkane, RX, where the leaving group is halide, X–. Different halides, though, have different leaving group abilities. The leaving group ability of X– is determined by two factors. • The strength of the C-X bond. The weaker the bond, the better the leaving group. The strength of the bond depends on the amount of orbital overlap between C and X. C is a small element, so the overlap decreases as the size of X increases, i.e. F > Cl >> Br >> I. • The polarization of the C–X bond. The more polarized the bond, the better the leaving group. The bond polarization decreases with decreasing electronegativity of X, i.e. in the order F > Cl > Br >> I. The actual order of leaving group ability is I– > Br– > Cl– >> F–.3 In fact, alkyl fluorides are nearly inert to substitution or elimination (hence the stability of Teflon). Other electronegative groups, e.g. RO–, can also act as leaving groups in principle. Comparing F– and HO–, both are about the same size, but F– is more electronegative. So we can conclude that HO– is a worse leaving group than F–. Since F– is already a very bad leaving group, HO– must be a really bad leaving group. HO– usually leaves only when the mechanism is E1cb, which we haven't discussed, or when extremely harsh conditions are used (i.e., 50% aq. KOH). There are several ways to make HO- is better leaving group: (1) Protonate the alcohol with a strong acid to get the conjugate acid of the alcohol. E.g. Et-OH + H-Br Et-OH2 + Br-+Br-+OH2CH3CHHBr CCH3HH+ H2O This converts a poor leaving group HO- into the pretty good leaving group OH2 (leaving group ability ≈ Cl–). Alcohols ROH are weak bases, with pKa of their conjugate acids ROH2+ ≈ 0, so an alcohol ROH is only protonated under acidic conditions to give ROH2+, an electrophile with a pretty good leaving group. This does not happen under basic conditions. Alcohols are electrophiles under acidic conditions, but not under basic conditions. (2) Replace the H in HO– with more electronegative groups. When H is replaced with RS(O)2, one obtains a very important class of leaving groups, the sulfonate esters. The most common sulfonates, RSO3–, are tosylate (short for toluenesulfonate, –OTs) and mesylate (-OMs, short for methanesulfonate). Tosylates and mesylates are easily4 made from alcohols and tosyl chloride TsCl or mesyl chloride MsCl. The O of the alcohol acts as a nucleophile toward electrophilic S, displacing the leaving group Cl– by an SN2 substitution reaction. The conversion of an alcohol to a tosylate represents a way of
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