CHEMISTRY. Module No and Title Module-, Electrophilic Aromatic Substitution: The ortho/para ipso attack, orientation in other ring systems.

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1 Subject Chemistry Paper No and Title Paper-5, Organic Chemistry-II Module No and Title Module-, Electrophilic Aromatic Substitution: The ortho/para Module Tag CHE_P5_M29

2 TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Electronic effects of the substituent 3.1 R = O, NR 2, NHR, NH 2, OH, OR, NHCOR, OCOR 3.2 R = NO 2, CN, SO 3 H, CHO, COR, CO 2 H, CONH R = + NR 3, + NH 3, CCl 3, CF R = Alkyl or Phenyl 3.5 R = Carboxylate Anions, CO R = F, Cl, Br, I 4. Effects of more than one substituent 5. Ipso-substitution 6. Orientation in other ring systems 7. Summary

3 1. Learning Outcomes After studying this module, you shall be able to Know various possibilities in electrophilic aromatic substitutions of substituted benzenes Learn about ortho, para, meta and ipso substitutions Familiarize with groups that either direct o/p-substitution or are m-directing Acquire an understanding of the observed orientation of the EAS products in benzene and other ring systems 2. Introduction When substituted benzenes undergo electrophilic substitution reactions, then there are usually 3 possibilities: the substitution may occur either at ortho or para or meta-position to the original substituents. Also, sometimes, a fourth type of substitution may be encountered viz. ipso substitution, a special case of electrophilic aromatic substitution where the leaving group is not hydrogen but the original substituent itself. These 4 possibilities are illustrated in the following figure: For example, consider the nitration reaction of the following substrates:

4 As can be seen, toluene gave a mixture of ortho and para-substitution products, while, nitrobenzene gave, predominantly, the meta-substitution product. The rate of the latter reaction is very slow as compared to the former one. A natural question arises, What are the influences of the original substituent in aromatic ring which leads to such observed product ratios? The answer(s) to this can be found out by studying the electronic nature of the substituent and its effects on the aromatic ring. 3. Electronic effects of the substituent Based on the observed pattern of electrophilic aromatic substitutions of a wide range of monosubstituted benzenes (R-C 6 H 5 ), the substituent R falls into the following categories: O, NR 2, NHR, NH 2, OH, OR, NHCOR, OCOR NO 2, CN, SO 3 H, CHO, COR, CO 2 H, CONH 2 + NR 3, + NH 3, CCl 3, CF 3 Alkyl/Phenyl CO 2 F, Cl, Br, I These are now discussed one-by-one in the following sections: 3.1 X = O, NR 2, NHR, NH 2, OH, OR, NHCOR, OCOR These groups (with the exception of O ), show an electron-withdrawing inductive effect ( I effect) as the atom directly attached to the benzene ring is more electronegative than carbon. On the other hand, there is also a strong +R (resonance) effect since each of these groups has a lone pair of electrons which they are able to donate to the ring via resonance.

5 +R >> I, for O, NR 2, NHR, NH 2, OH, OR +R > I, For NHCOR, OCOR Thus, these groups make the ring more electron rich than benzene and hence making the ring more susceptible to attack by electrophiles. Thus, aromatic rings bearing these groups react faster than benzene and the groups are said to be activating, in the following decreasing order of reactivity: O > NR 2 > NHR > NH 2 > OH > OR > NHCOR > OCOR (The latter two are less activating than the others because the lone pairs on the hetero-atom are to some extent also being delocalised into the carbonyl group). Now, to explain the orientation in these cases, as can be seen from the preceding figure, the resonance effect builds up negative charge only on the ortho and para positions in the starting material. Thus, one can expect the electrophile to attack these positions selectively. Also, if one may consider the formation and stabilization of the Wheland complexes (σ-complex) of the three possible mode of electrophilic attack, the same conclusion is reached. The same is explained in the case of anisole as shown below: As illustrated, for the attack at either ortho or para positions, the Wheland intermediate has an extra canonical form in which the positive charge is delocalised onto the O-atom by involvement

6 of the lone pair on O. This is not possible on attack at the meta position and hence the meta-attack intermediate is less stable than those from either ortho or para. (However, steric effects also come to play and hence the ratio of the ortho to para product is ~1:2 for anisole). Thus, these groups are activating and ortho, para directing. 3.2 X = NO 2, CN, SO 3 H, CHO, COR, CO 2 H, CONH 2 These groups show a moderate to strong electron-withdrawing inductive effect, ( I effect) as these possess a partial to full positive charge on the atom directly attached to the aromatic ring. They also display electron-withdrawing resonance effects, R. These effects are illustrated below for the case of nitrobenzene: In effect, they make the aromatic ring electron-poor in comparison to benzene, and thereby, act as strongly deactivating groups i.e. reactions proceed much slower in rings bearing these groups compared to benzene. Also, the orientation of the resulting product can be predicted in two ways: (i) Presence of positive charges at the ortho and para positions in the resonance hybrids as shown above for nitrobenzene will dissuade the electrophile to attack at these positions. Hence, meta product will mainly predominate as only the meta position is now available for the electrophile to attack. (ii) By comparing the stability of the Wheland intermediates:

7 As shown, while the attack at the ortho or para positions will lead to one canonical form, wherein, a positive charge is situated adjacent to the positively charged substituent, which is unfavourable electrostatically, such a situation is avoided in meta attack. Hence, these groups will be deactivating and meta directing. 3.3 X = + NR 3, + NH 3, CCl 3, CF 3 These groups also show a strong electron-withdrawing inductive effect ( I) due to their positive charge or because of the strong electronegativity of the halogens (which leads to a positive polarization of the atom directly attached to the aromatic ring). However, there is no resonance effect as there are no orbitals or electron pairs which can overlap with those of the ring. The inductive effect creates small positive charges on the ortho and para positions but not on the meta position and it destabilises the Wheland intermediate. Hence these groups are deactivating and meta-directing. This is illustrated in the figures below:

8 So, for the deactivating, meta-directing groups (discussed in 3.2 and 3.3) the effect in the decreasing order is as shown below: 3.4 X = Alkyl or Phenyl Since, there is a weak electronegativity difference between the carbon atom of the alkyl group and its hydrogen atoms, the C-atom becomes more electron-rich and it passes this electronic current to the aromatic ring. Thus, there is a weak inductive effect (+I). Also, weak resonance effects from hyperconjugation also increase the electron density in the ring.

9 These two effects will thus aid the attack of the electrophile, albeit weakly, and so alkyl groups should be mildly activating. Also, these are weak ortho and para directing groups, as can be seen by the resonance hybrids of the substrate (shown above) or by the stabilization of the Wheland intermediates as shown below for the ortho-attack: In case of a phenyl substituent, resonance stabilization of the Wheland intermediate for ortho and para electrophilic attack takes place, and so, these are also weakly activating and o-/p- directing. 3.5 X = Carboxylate Anions, CO 2 There is an almost zero resonance effect since the negative charge of the anion is itself delocalized with the carbonyl group. So, there is no electron withdrawing resonance effect. The negatively charged carboxylate ion moderately repels the electrons in the bond attaching it to the ring. Thus, there is moderate electron-donating +I effect producing small negative charges on the ortho and para positions but not on the meta position. So, overall the carboxylate group has a weak activating influence on the aromatic ring and are o-/p- directing. Similar argument can be applied for the stabilisation of the Wheland intermediate.

10 3.6 X = F, Cl, Br, I Consider the nitration of chlorobenzene: The reaction is much slower than benzene, and ortho and para products are mainly formed. To justify these effects, consider the properties of the halogens. These are powerful electronwithdrawing elements (being very electronegative) and thus show a strong I effect, thereby, deactivating the ring for electrophilic attack. However, the halogens also have lone pairs of electrons that they can donate via resonance in the σ-complexes for ortho- and para- electrophile attack, while the reaction at the meta- position does not allow for the positive charge to be placed next to to the halogen, and therefore does not result in any stabilization. The canonical forms of σ-complex for para- electrophile attack is shown below: Thus, these groups are deactivating but o/p directing. 4. Effects of more than one substituent The cumulative effects of both the substituents have to be taken into account and it is often possible to predict the correct isomer of electrophilic aromatic substitution, especially, when

11 groups on the ring reinforce their directing abilities. For example, consider the following compounds: In the molecule A, where both the -OMe and -Cl are o/p-directing will cumulatively guide the incoming electrophile to the ortho/para positions as marked above. Similarly, in molecule B, both -COOH group and -NO 2 are m-directing and will guide the incoming electrophile to only one of the m-position as marked in the figure. However, in molecule C, where the groups oppose each other, it is more difficult and one often gets a mixture. However, there are some general rules for prediction of the orientation: We can arrange the groups in the following order of influence: O-, NR 2, NHR, NH 2, OH, OR > NHCOR, OCOR > R > F, Cl, Br, I > all m- directing groups Due to steric reasons, the electrophile is less likely to attack between two groups. When an o-/p- directing is meta to a meta-directing group the electrophile goes predominantly ortho to the meta directing group rather than para to it. 5. Ipso-substitution There is also a possibility of electrophilic attack at the ring carbon-atom to which the substituent X is attached. So, substitution of the original substituent by the electrophile is termed as ipso substitution.

12 As can be logically anticipated, ipso substitution will be promoted by those substituents (X) which can form stable X + cation after attack by the electrophile. Thus substituents such as: Br, I, SiR 3, SnR 3, R (usually secondary/tertiary alkyls) undergo electrophilic aromatic substitutions with predominant ipso product. Some examples of ipso substitutions are provided below: Also, protodesulfonylation occurs, where the electrophile H +, replaces the substituent SO 3 which subsequently is hydrated to form H 2 SO 4. However, the ipso attack can theoretically have five possible fates: electrophile migration, ipso group migration, ipso group loss, electrophile loss, nucleophile addition. This is shown below:

13 H Nu E X -E+ E -X+ X X H E E X E H X 6. Orientation in other ring systems In naphthalene, there are only two possible sites for substitution: 1 (α) and 2 (β). (all others are equivalent to 1 and 2). However, electrophilic substitution predominantly occurs at C-1 than C-2. This can be explained on the basis of stabilization of the respective σ-complexes: Attack at C-1 (stabilization by allylic resonance; benzenoid character of other ring is maintained) Attack at C-2 (the benzenoid character of the other ring is sacrificed for stabilization of the +ve charge by resonance) Similarly, in Anthracene, electrophilic substitution occurs at the middle ring via intermediate-a. This is due to the fact that intermediate-a has one resonating structure preserving two benzenoid rings which is lacking in other modes of attack.

14 For hetero-aromatic systems such as pyridine, furan, pyrrole etc., no generalizations can be made. However, each group has to be studied differently. Pyridine reacts very slowly towards EAS and its reactivity resembles that of nitrobenzene as the presence of electronegative N-atom in ring causes π electrons to be held more strongly than in benzene. EAS takes place at C-3. For eg. sulfonation of pyridine at high temperatures is shown below: Pyrrole, Furan, and Thiophene are relatively reactive towards EAS as total 6π electrons are present in delocalised π-orbitals shared between 4 carbons and one hetero-atom (lone pair). Thus, these are π-excessive heterocycles and π electrons are held less strongly. Substitution at C-2 is favoured over C-3. For example, pyrrole undergoes nitration at C-2. Nitration at 3-position It can be clearly seen from the above resonating structures for nitration at C-2 and C-3 respectively that substitution at C-2 has more resonating structures. Thus, C-2 position is favoured.

15 7. Summary When substituted benzene compounds undergo electrophilic substitution reactions, then there are total 4 possibilities: the substitution may occur either at ortho or para or metaposition to the original substituents or ipso substitution may occur. Electron donating substituents, X = O, NR 2, NHR, NH 2, OH, OR, NHCOR, OCOR are activating and ortho, para directing. Electron-withdrawing substituents NO 2, CN, SO 3 H, CHO, COR, CO 2 H, CONH 2 are deactivating and meta directing. + NR 3, + NH 3, CCl 3, CF 3 are also de-activating and meta directing as these also show strong electron-withdrawing I effect. Alkyl or Phenyl groups are mildly activating and o-/p- directing due to hyperconjugation and resonance effects respectively. Carboxylate anions, CO 2 show weak activating influence on the aromatic ring and are o- /p- directing as there is moderate electron-donating +I effect. Halogens F, Cl, Br, I, being very electronegative, show a strong I effect and are deactivating. However, they are o-/p- directing by virtue of their lone pair of electrons which they can donate during resonance stabilization of the intermediates. When two substituents are present on the ring, the cumulative effects of both the substituents have to be taken into account and it is often possible to predict the correct isomer of electrophilic aromatic substitution when they are reinforcing each other s effects. Substitution of the original substituent by the electrophile is termed as ipso substitution and commonly encountered with substituents such as: Br, I, SiR 3, SnR 3, R (usually secondary/tertiary alkyls) and SO 3 H. Orientation in other ring systems including hetero-aromatic systems can be predicted on similar lines by considering the resonating structures of the σ-complexes.