However, a water molecule encountering the carbocation intermediate could alternatively act as a base rather than as a nucleophile, plucking a proton from one of the methyl carbons and causing the formation of a new carbon-carbon p bond. This alternative pathway is called an elimination reaction, and in fact with the conditions above, both the substitution and the elimination pathways will occur in competition with each other.
Elimination can be minimized by keeping the reaction cold, but some of this side-reaction is often inevitable. These will be covered very soon, in section 8. If the carbocation can easily rearrange to a more stable carbocation, then rearrangement products are likely to be important, and the reaction may lead to mixtures.
The rates of S N 1 reactions are generally increased by the use of a highly polar solvent, including protic hydrogen bonding solvents such as water or ethanol. In essence, a protic solvent increases the reactivity of the leaving group in an S N 1 reaction, by helping to stabilize the products of the first ionization step. In the S N 1 mechanism, remember, the rate determining step does not involve the nucleophilic species, so any reduction of nucleophilicity does not matter.
What matters is that the charged products of the first step — the carbocation intermediate and the anionic leaving group — are stabilized best by a highly polar, protic solvent. When considering whether a nucleophilic substitution is likely to occur via an S N 1 or S N 2 mechanism, we really need to consider three factors:. When the leaving group is attached to a tertiary, allylic, or benzylic carbon, a carbocation intermediate will be relatively stable and thus an S N 1 mechanism is favored.
Weaker nucleophiles such as water or alcohols favor the S N 1 mechanism. Polar protic solvents favor the S N 1 mechanism by stabilizing the carbocation intermediate. S N 1 reactions are frequently solvolysis reactions. Because substitution occurs at a chiral carbon, we can also predict that the reaction will proceed with racemization. In the reaction below, on the other hand, the electrophile is a secondary alkyl bromide — with these, both S N 1 and S N 2 mechanisms are possible, depending on the nucleophile and the solvent.
In this example, the nucleophile a thiolate anion is strong, and a polar protic solvent is used — so the S N 2 mechanism is heavily favored. The reaction is expected to proceed with inversion of configuration. Determine whether each substitution reaction shown below is likely to proceed by an S N 1 or S N 2 mechanism. Skip to main content. Search for:. Factors affecting the S N 2 reaction As we saw in the previous section, in the S N 2 reaction the rate of reaction depends on both the electrophile usually an alkyl halide and the nucleophile.
This leads to the following reactivity order for alkyl halides Practically, alkyl fluorides are not used for S N 2 reactions because the C-F bond is too strong. Stability of the group after leaving When the C-X bond breaks in a nucleophilic substitution, the pair of electrons in the bond goes with the leaving group. Factors favoring S N 2 To design an effective S N 2 reaction using an alkyl halide, we need: An unhindered alkyl halide preferably methyl or primary, but secondary may be possible A good leaving group preferably I or Br A strong nucleophile A suitable solvent — polar aprotic is most effective.
The electrophile This topic was examined in general in section 6. Stability of carbocation intermediates We know that the rate-limiting step of an S N 1 reaction is the first step — formation of the this carbocation intermediate. Factors favoring S N 1 To design an effective S N 1 reaction using an alkyl halide, we need: A highly substituted alkyl halide preferably tertiary or resonance-stabilized, but secondary may be possible , ideally one which will not lead to rearrangement A good leaving group preferably I or Br A non-basic nucleophile to reduce the elimination side reaction A suitable solvent — polar protic is most effective.
When considering whether a nucleophilic substitution is likely to occur via an S N 1 or S N 2 mechanism, we really need to consider three factors: 1 The electrophile: when the leaving group is attached to a methyl group or a primary carbon, an S N 2 mechanism is favored here the electrophile is unhindered by surrounded groups, and any carbocation intermediate would be high-energy and thus unlikely.
Exercise Determine whether each substitution reaction shown below is likely to proceed by an S N 1 or S N 2 mechanism. Show Solution a S N 2 primary electrophile, strong nucleophile, polar aprotic solvent b S N 1 tertiary electrophile, weak nucleophile, protic solvent c S N 2 secondary electrophile, strong nucleophile, polar protic solvent. Licenses and Attributions. CC licensed content, Shared previously. Author information Article notes Copyright and License information Disclaimer.
Corresponding author. Received Dec This article has been cited by other articles in PMC. Abstract The reaction potential energy surface PES , and thus the mechanism of bimolecular nucleophilic substitution S N 2 , depends profoundly on the nature of the nucleophile and leaving group, but also on the central, electrophilic atom, its substituents, as well as on the medium in which the reaction takes place.
Keywords: bimolecular nucleophilic substitutions S N 2 , hypervalency, organic chemistry, potential energy surface, reaction barriers. Open in a separate window. Scheme 1. Scheme 2. Scheme 3. A general representation of the competition between S N 2 and E2 mechanisms. Variation of Nucleophile and Leaving Group 2. Scheme 4. Scheme 5. Other Small Nucleophiles and Leaving Groups There are a number of studies that focus on other nucleophiles and leaving groups.
Figure 1. Bulky Nucleophiles and Leaving Groups In addition to the smaller nucleophiles described above, larger ones have been systematically studied as well. Scheme 6. Scheme 7.
Figure 2. Figure 3. Scheme 8. S N 2 S A number of studies have focused on S N 2 reactions at sulfur, involving numerous combinations of nucleophiles and leaving groups. Scheme 9. Scheme Creation of Pentavalent Carbon The propensity to localize or delocalize bonds is an important issue for the design of truly pentavalent carbon compounds.
Outlook Bimolecular nucleophilic substitution S N 2 reactions are fundamentally simple and ubiquitous processes that are central to a wide range of organic, biochemical, and biological transformations. Conflict of interest The authors declare no conflict of interest. Biographical Information Trevor A. Biographical Information Marcel Swart obtained his Ph. Notes T. Contributor Information Prof. References 1. Walden P. Carey F.
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Valero R. Correra T. Kretschmer R. Itoh S. Lee S. Liang J. Proenza Y. Ren Y. Of course, there are many other noncovalent interactions between active site enzyme residues and the substrate the adenine base and cofactor SAM , but in the interest of clarity these are not shown. These interactions, many of which are hydrogen-bonds, help to position the adenine base and SAM in just the right relative orientation inside the active site for the nucleophilic attack to take place.
If you have access to American Chemical Society journals, a paper about an enzyme catalyzing a similar N-methylation reaction contains some detailed figures showing hydrogen-bond and charge-dipole interactions between the enzyme active site and the two substrates: see Biochemistry , 42, , figure 4. The electrophile is a methyl carbon, so there is little steric hindrance to slow down the nucleophilic attack. The carbon is electrophilic electron-poor because it is bonded to a positively-charged sulfur, which is a powerful electron withdrawing group.
The positive charge on the sulfur also makes it an excellent leaving group, because as it leaves, it becomes a neutral and very stable sulfide. All in all, we have a good nucleophile enhanced by the catalytic base , an unhindered electrophile, and an excellent leaving group. Notice something else about the SAM methylation mechanism illustrated in the previous figure.
It is termolecular: there are three players acting in concert: the catalytic base, the nucleophile, and the electrophile. This is possible because the all three players are bound in a very specific geometry in the active site of the enzyme. In a reaction that takes place free in solution, rather than in an active site, the likelihood of three separate molecules colliding all at once, with just the right geometry for a reaction to take place, is very, very low.
You should notice going forward that when we illustrate the mechanism of a reaction that takes place free in solution, we will only see bimolecular steps - two molecules colliding. Almost all of the biochemical reactions we see in this book will be enzyme-catalyzed - and termolecular steps will be common - while almost all of the laboratory reactions we see will take place free in solution, so we will only see unimolecular and bimolecular steps.
Synthetic chemists often employ non-biological catalysts that mimic enzyme active sites, but these examples are well beyond the scope of our discussion. Considering periodic trends in acidity and basicity, what can you say about the relative basicity of a sulfide?
The substrate here is epinephrine, also known as adrenaline, and the reaction is part of the pathway by which adrenaline is degraded in the body.
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