The mechanism of nucleophilic aromatic substitution, however, is different than what we learned in the S N 1 and S N 2 reactions. And this can be explained by the selective addition of the amide nucleophile to the benzyne such that only the more stable carbanion is formed: The first carbanion is stabilized by the highly electronegative trifluoromethyl group through an inductive effect since the electron pair in the sp2 orbital does not overlap with the π orbitals of the aromatic system. Be sure to specify stereochemistry. Anything which removes electron-density from the nucleophilic atom will make it less nucleophilic. So, no SN1 or SN2 in nucleophilic aromatic substitutions! The backside attack results in inversion of configuration, where the product's configuration is opposite that of the substrate. The Meisenheimer complex is not stabilized when the EWG group is meta to the leaving group. If the cis configuration is the substrate, the resulting product will be trans. A backside nucleophilic attack results in inversion of configuration, and the formation of the R enantiomer. Approach from the front side simply doesn't work: the leaving group - which is also an electron-rich group - blocks the way. Watch the recordings here on Youtube! In nucleophilic sub… This will be covered in detail soon, in section 8.5. Legal. As long as the two of the groups attached to the carbon being attacked are small hydrogens, the repulsions which happen do not require much energy. The β is the ortho position for aromatic compounds and that’s the most acidic proton which is eliminated by the hydroxide (or other bases) ion in the first step: The negative charge then is stabilized by the inductive effect of the halogen which is eventually kicked out by this lone pair generating the highly reactive benzyne intermediate. Within a column, size of atom. For example, the reaction below has a tertiary alkyl bromide as the electrophile, a weak nucleophile, and a polar protic solvent (we’ll assume that methanol is the solvent). In section 6.5, we learnt what makes a nucleophile strong (reactive) or weak (unreactive). A backside nucleophilic attack results in inversion of configuration, and the formation of the S enantiomer. In the term SN2, S stands for 'substitution', the subscript N stands for 'nucleophilic', and the number 2 refers to the fact that this is a bimolecular reaction: the overall rate depends on a step in which two separate molecules (the nucleophile and the electrophile) collide. The addition of a third R group to this molecule creates a carbon that is entirely blocked. The charge is closer to the EWG, therefore the nucleophile is farther away from it! In this way, the leaving group is analogous to the conjugate base in a Brønsted-Lowry acid-base reaction. When the leaving group is attached to a tertiary, allylic, or benzylic carbon, a carbocation intermediate will be relatively stable and thus an SN1 mechanism is favored. Again these are determined by the C-X bond strength and the stability of X after it has left. In conclusion, SN2 reactions that begin with the R enantiomer as the substrate will form the S enantiomer as the product. If we have a strong nucleophile, the SN2 reaction will happen faster; a weak nucleophile will react more slowly and may not even react. Fluoride is the least effective leaving group among the halides, because fluoride anion is the most basic. However, some aryl halides with a strong electron-withdrawing substituent(s) on the ring can undergo nucleophilic substitution (SNAr) instead of electrophilic substitution: X here is the leaving group and the EWG stands for electron-withdrawing group which is there to activate the ring by making it electron-deficient. a nucleophile. We know that the rate-limiting step of an SN1 reaction is the first step – formation of the this carbocation intermediate. To think about why this might be true, remember that the nucleophile has a lone pair of electrons to be shared with the electrophilic center, and the leaving group is going to take a lone pair of electrons with it upon leaving. All of the concepts that we used to evaluate the stability of conjugate bases we can use again to evaluate leaving groups. This leads to the following reactivity order for alkyl halides. Why Are Halogens Ortho-, Para- Directors yet Deactivators ? The fact that the atom adjacent to the carbonyl carbon in carboxylic acid derivatives is an electronegative heteroatom – rather than a carbon like in ketones or a hydrogen like in aldehydes - is critical to understanding the reactivity of these functional groups. There are two main factors: The strength of the C-X bond, and the stability of the X group after it has left. Unlike the previous example, there is only one product formed in this reaction. These will be covered very soon, in section 8.4. In other words, the trends in basicity are parallel to the trends in leaving group potential – the weaker the base, the better the leaving group. This is called an 'SN2' mechanism. As each hydrogen is replaced by an R group, the rate of reaction is significantly diminished. (In all figures in this section, 'X' indicates a halogen substituent). We are going to talk about the details of the mechanism below but for now, let’s also mentions that the reactivities of aryl halides increases, depending on the leaving group, in the following order: So, the more electronegative the halogen, the better leaving group it is in a nucleophilic aromatic substitution. So, comparing these two reactions to summarize the regiochemistry of nucleophilic aromatic substitution, we can say that when no electron-withdrawing group is present on the ring, a mixture of isomers is obtained, except if there are no ortho hydrogens next to the halogen (no acidic proton) in which case the reaction does not occur. To design an effective SN2 reaction using an alkyl halide, we need: As we learnt in section 8.2, the nucleophile has no effect on the rate of an SN1 reaction. But a electrophile that is good for SN2 is not necessarily good for SN1, for reasons that will become clear. In the case of bimolecular nucleophilic substitution, these two reactants are the haloalkane and the nucleophile. In essence, a protic solvent increases the reactivity of the leaving group in an SN1 reaction, by helping to stabilize the products of the first (ionization) step. Nucleophilic substitution is the reaction of an electron pair donor (the nucleophile, Nu) with an electron pair acceptor (the electrophile). What is the reason for this change of reactivity and, in general, what is the mechanism of nucleophilic aromatic substitution? We will be contrasting about two types of nucleophilic substitution reactions. First, we have a two-step β elimination. If each of the three substituents in this transition state were small hydrogen atoms, as illustrated in the first example below, there would be little steric repulsion between the incoming nucleophile and the electrophilic center, thereby increasing the ease at which the nucleophilic substitution reaction can occur. Chemical reactions in haloalkanes primarily fall into 3 different categories. If R groups were added to carbons farther away from the electrophilic carbon, we would still see a decrease in the reaction rate. When an electron-withdrawing group is present on the ring, the negative charge is formed on the carbon which is closest to the EWG group and the nucleophile appears on the adjacent carbon: To make a shortcut for predicting the regiochemistry of nucleophilic aromatic substitution via the benzyne intermediate, remember that the nucleophile ends up on the carbon which is farther away from the EWG group. The key factor is that aryl halides cannot undergo an S N 2 by a backside attack of the nucleophile and, unlike S N 1, the loss of the leaving group cannot occur since the phenyl cations are very unstable: A carbocation is a very potent electrophile, and the nucleophilic step occurs very rapidly compared to the first (ionization) step. Another feature of the SN1 reaction is that it is often prone to side reactions, which is why it is less used in synthesis than the SN2 reaction.