The SN2 Mechanism

The reactio G witlp(yjj OQpj. i ij t Ql gf 8 2 reaction. What are the general features of iTiSaittiismf 

An Sn2 reaction exhibits second-order kinetics that is, the reaction is bimolecular and both the alkyl halide and the nucleophile appear in the rate equation. 

Changing the concentration of either reactant affects the rate. For example, doubling the concentration of either the nucleophile or the alkyl halide doubles the rate. Doubling the concentration of both reactants increases the rate by a factor of four. 

What happens to the rate of an 3 2 reaction under each of the following conditions  

The most straightforward explanation for the observed second-order kinetics is a concerted reaction—bond breaking and bond making occur at the same time, as shown in Mechanism 7.1. 

To understand these differences, we must consider the mechanisms by which the substitutions in Table 6.1 take place. 

As a result of experiments that began more than 70 years ago, we now understand the mechanisms of nucleophilic substitution reactions rather well. We use the plural because such nucleophilic substitutions occur by more than one mechanism. The mechanism observed in a particular case depends on the structures of the nucleophile and the alkyl halide, the solvent, the reaction temperature, and other factors. 

There are two main nucleophilic substitution mechanisms. These are described by the symbols Sf.,2 and S l, respectively. The part of each symbol stands for substitution, nucleophilic. The meaning of the numbers 2 and 1 will become clear as we discuss each mechanism. 

The 8 2 mechanism is a one-step process, represented by the following equation  

The n2 mechanism is a one-step process in which the bond to the ieaving group begins to break as the bond to the nucleophile begins to form. 

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Reaction of Primary Alcohols with Hydrogen Halides The Sn2 Mechanism... 

REACTION OF PRIMARY ALCOHOLS WITH HYDROGEN HALIDES THE Sn2 MECHANISM... 

FIGURE 8 2 Hybrid orbital description of the bonding changes that take place at carbon during nucleophilic substitution by the Sn2 mechanism... 

Reactivity of Some Alkyl Bromides Toward Substitution by the Sn2 Mechanism ... 

As we have seen the nucleophile attacks the substrate m the rate determining step of the Sn2 mechanism it therefore follows that the rate of substitution may vary from nucleophile to nucleophile Just as some alkyl halides are more reactive than others some nucleophiles are more reactive than others Nucleophilic strength or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate By measuring the rate at which various Lewis bases react with methyl iodide m methanol a list of then nucleophihcities relative to methanol as the standard nucleophile has been compiled It is presented m Table 8 4... 

Having just learned that tertiary alkyl halides are practically inert to substitution by the Sn2 mechanism because of steric hindrance we might wonder whether they undergo nucleophilic substitution at all We 11 see m this section that they do but by a mecha nism different from 8 2... 

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

Aryl halides react too slowly to undergo substitution by the Sn2 mechanism with the sodium salt of diethyl malonate and so the phenyl substituent of phenobarbital cannot be introduced in the way that alkyl substituents can... 

The Sn2 mechanism is believed to describe most substitutions in which simple primary and secondary alkyl halides react with anionic nucleophiles. All the exanples cited in Table 8.1 proceed by the Sn2 mechanism (or a mechanism very much like Sn2— remember, mechanisms can never be established with certainty but represent only our best present explanations of experimental observations). We ll examine the Sn2 mechanism, particularly the stnacture of the transition state, in more detail in Section 8.5 after-first looking at some stereochemical studies cariied out by Hughes and Ingold. 

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. 

Rate is governed by stability of car-bocation that is formed in ionization step. Tertiary alkyl halides can react only by the SnI mechanism they never react by the Sn2 mechanism. (Section 8.9) Rate is governed by steric effects (crowding in transition state). Methyl and primary alkyl halides can react only by the Sn2 mechanism they never react by the SnI mechanism. (Section 8.6)... 

Allyl chloride is quite reactive toward nucleophilic substitutions, especially those that proceed by the Sn2 mechanism, and is used as a starting material in the synthesis of a variety of drugs and agricultural and industrial chemicals. 

Hydrolysis of (/ )-( —)-2-bromooctane by the Sn2 mechanism yields optically active (S)-(+)-2-octanol. The 2-octanol obtained by hydrolysis of racemic 2-bromooctane is not optically active. 

The real world of Sn reactions is not quite as simple as the discussion has so far suggested. The preceding treatment in terms of two clearly distinct mechanisms, SnI and Sn2, implies that all substitution reactions will follow one or the other of these mechanisms. This is an oversimplification. The strength of the dual mechanism hypothesis and its limitations are revealed by these relative rates of solvolysis of alkyl bromides in 80% ethanol methyl bromide, 2.51 ethyl bromide, 1.00 isopropyl bromide, 1.70 /er/-butyl bromide, 8600. Addition of lyate ions increases the rate for the methyl, ethyl, and isopropyl bromides, whereas the tert-butyl bromide solvolysis rate is unchanged. The reaction with lyate ions is overall second-order for methyl and ethyl, first-order for tert-butyl, and first- or second-order for the isopropyl member, depending upon the concentrations. Similar results are found in other solvents. These data show that the methyl and ethyl bromides solvolyze by the Sn2 mechanism, and tert-butyl bromide by the SnI mech-... 

Not all models are physical or pictorial objects. For example, the Sn2 mechanism is a simple model for a particular class of reactions that successfully explains a lot of chemistry. What all of these things have in common is that they use a set of pre-defined objects and rules to approximate real chemical entities and processes. 

A treatise on kinetics is a logical and fitting medium in which to analyze and discuss just such limitations and uncertainties of mechanism. The present chapter will attempt such a treatment for the SN2 mechanism in nucleophilic aromatic substitution. An effort will be made to pinpoint every assumption and highlight every instance where alternate choices are possible. The end result hoped for is a clearer delineation of the known and the probable from the uncertain and the unknown. 

Conversion at the chiral center if the mechanism is known. Thus, the Sn2 mechanism proceeds with inversion of configuration at an asymmetric carbon (see p. 390) It was by a series of such transformations that lactic acid was related to alanine ... 

One type of process that can successfully be treated by the Marcus equation is the Sn2 mechanism (p. 390)... 

There is a large amount of evidence for the Sn2 mechanism. First, there is the kinetic evidence. Since both the nucleophile and the substrate are involved in the rate-determining step (the only step, in this case), the reaction should be first order in each component, second order overall, and satisfy the rate expression... 

Another kind of evidence for the Sn2 mechanism comes from compounds with potential leaving groups at bridgehead carbons. If the Sn2 mechanism is correct, these compounds should not be able to react by this mechanism, since the... 

For a list of some of the more important reactions that operate by the Sn2 mechanism, see Table 10.7. 

Like the kinetic evidence, the stereochemical evidence for the SnI mechanism is less clear-cut than it is for the Sn2 mechanism. If there is a free carbocation, it is planar (p. 224), and the nucleophile should attack with equal facility from either side of the plane, resulting in complete racemization. Although many first-order substitutions do give complete racemization, many others do not. Typically there is 5-20% inversion, though in a few cases, a small amount of retention of configuration has been found. These and other results have led to the conclusion that in many SnI reactions at least some of the products are not formed from free carbocations but rather from ion pairs. According to this concept," SnI reactions proceed in this manner ... 

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