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7.14.1 Substitution in a previously monosubstituted benzene derivative

There are five possible substitution positions in a monosubstituted benzene derivative.

So, what happens when this benzene derivative undergoes a second substitution reaction i.e. where does the second substituent go in the benzene ring? and why does the substituent end up in that position on the benzene ring?

The diagram below illustrates the situation, where the initial substituent group is shown as G (and for the rest of this page).

Obviously there are five possible positions in the benzene ring for an electrophile to attack - denoted by the carbon ring numbers 2 to 6, for the possible 2nd substituent position (the original substituent is by convention, position 1.)

If we assume for a 2nd substituent into the benzene ring from an electrophilic substitution reaction:

(i) the electron density is the same for positions 2 to 6, i.e. assuming group G has no effect on the π orbitals,

(ii) completely random attack collisions of the electrophile i.e. equal probability of hitting any of the π electron cloud adjacent to one of carbon atoms 2 to 6,

(iii) positions 2 and 6 are equivalent and positions 3 and 5 are equivalent too (molecular symmetry, and the only assumption which is actually true!),

(iv) there is no steric hindrance of the nucleophilic attack by the pre-existing substituent group G e.g. most likely to affect benzene ring positions 2 and 6 closest to the substituent G group.

On this hypothetical basis you would expect an electrophilic substitution reaction of a monosubstituted benzene derivative to yield the following:

40% substitution at ring carbon atom 2 (= 6),

40% substitution at ring carbon atom 3 (= 5), and,

20% substitution at ring carbon atom 4.

BUT, this is not what you find in the products from aromatic electrophilic substitution reactions.

You can see this from the data table below of TYPICAL YIELDS from further substitution of monosubstituted benzene derivatives.

KEY to three important abbreviations with reference to electrophilic substitution in monosubstituted benzene derivatives:  

(A24) In these molecules the benzene ring is activated by substituent group G compared to benzene and tends to direct the 2nd substituent to the 2 or 4 position in the benzene ring. See section 7.14.2

(D24) In these molecules the benzene ring is moderately deactivated by substituent group G compared to benzene, but still tends to direct the 2nd substituent to the 2 or 4 position in the ring. See section 7.14.3

(D3) In these molecules the benzene ring is more strongly deactivated by substituent group G compared to benzene, and tends to direct the 2nd substituent to the 3 position in the ring. See section 7.14.4

The reason being that, the 1st substituent group G has a profound effect on the π orbitals (in particular) i.e. the electron density and susceptibility to electrophilic attack of the other five carbon atoms of the benzene ring e.g.

If the carbon atom that is bonded by a sigma bond to the benzene ring also has a pi bond (e.g. >C-C=O), the electron density of the ring is reduced and substitution is more difficult, but less so in the 3 and 5 positions, where electrophilic substitution is more likely to take place.

If the atom that is bonded to the benzene ring does not have any pi bonding, but has at least one non-bonding pair of electrons, the electron density may be either increased (methylbenzene) or decreased (chlorobenzene)  BUT the electron density is relatively greater at the 2, 4 and 6 positions where electrophilic substitution is more likely to take place,

This in turns leads to the orientation of products (positions of 2nd substitution) that you might not expect.

The influence of the substituent group G on product orientation can be due to:

(a) the charge distribution can depends on the polar effect of G, +/- inductive effect.

Strongly electronegative groups reduce the reactivity (deactivate) the benzene ring.

However their effect is varied, the most electronegative groups often strongly deactivate the benzene ring, and orientate substitution to the 3 position.

But, less strongly electronegative groups reduce reactivity less and direct substituents to the 2 and 4 positions.

Also note that non-polar alkyl groups give a small +I effect to increase the electron density and hence the reactivity of the benzene ring.

(b) Sometimes a lone pair of electrons of the atom of G, or a pi bond system in G, which is directly attached to the benzene ring, gives rise to a resonance effect that can decrease or increases the electron densities in the 2, 4 and 6 positions.

These two factors can work in opposition or complement each other, and detailed explanatory arguments are beyond the scope of this page, neither have I gone into too detail on hyperconjugation and mesomeric effects.

However, I have used the concept of 'inductive' effect (+/- I), delocalisation of electrons, and drawn some resonance structures for selected molecules to:

(i)  help understand the relative reactivity of monosubstituted benzene derivatives compared to benzene itself and,

(ii) why certain positions on the benzene ring are most favoured for substitution, which usually means carbon atoms 2, 4, 6  or  3,5 sets of positions.

 

Examples of substituent group G and their orientation effect on the substitution products - three types of effect.

Data adapted from https://www2.chemistry.msu.edu/faculty/reusch/virttxtjml/chapt15.htm and other 'thick' textbook sources!

The following three sections now look at the three types of substituent groups and their effect, with examples explained in more detail, of the effect of the 'G' group.

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7.14.2 The effect of an activating group on substitution orientation in a monosubstituted benzene derivative - 2, 4 and 6 position directing groups (ortho and para substitution positions)

Certain substituent groups in a benzene ring can increase the electron density of the benzene ring and make the aromatic compound more reactive towards electrophiles.

The effect is 'partial', and seems to enhance the reactivity at the 2 and 4 carbon atom substitution positions more than the 3 substitution position for a 2nd hydrogen substituted group put into a benzene ring.

Groups that increase reactivity are e.g. methyl -CH₃, hydroxy (phenol) -OH, amino/amine -NH₂, acylated amine -NHCOCH₃, which greatly favour substitution at the 2 and 4 positions (often >90% combined and <10% for the 3 position).

This group of substituents all, by some means, have a small, but significant, electron donating (+I inductive effect) on the ring of pi electrons.

This is shown in the diagram below where I've indicated the 1st substituent group as G and its effect on the pi electron clouds - the subsequent effect of the susceptibility of the other 5 ring CH groups to electrophilic attack i.e. their relative reactivity - the activating or deactivating effect of G.

The diagrams above and below show the increase in electron density of C₆H₅-G compared to C₆H₆ and below a more specific diagram for methylbenzene showing the increased electron density at positions 2, 4 and 6 - the sites more susceptible to electrophilic attack.

(a) The nitration of methylbenzene

  +  HNO₃  ===>       +  H₂O

Typical results for nitrating methylbenzene with conc. nitric and sulfuric acids (electrophile NO₂⁺).

The theoretical percentage yields are quoted as if the methyl group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

The methyl group has a small, but significant +I inductive effect that increases the electron density of the benzene ring, particularly at the 2, 4 and 6 positions.

So, methylbenzene is significantly more reactive than benzene and when nitrated, 96% of the products are either methyl-2-nitrobenzene or methyl-4-nitrobenzene.

If the G group is -NO₂, you get deactivation.

The diagram below shows the 2, 4 and 6 activated sites on the methylbenzene molecule.

 

The nitration reactivity order is: methylbenzene  >  benzene  >  nitrobenzene

See also Electrophilic substitution - nitration of benzene and methylbenzene, properties and uses of nitro-aromatics

(b) The sulfonation of methylbenzene

Benzene and methylbenzene are insoluble in sulfuric acid, but the resulting sulfonic acids are soluble.

Therefore the sulfonation reaction is complete when the hydrocarbon layer disappears.

Using fuming sulfuric acid (extra SO₃ electrophile available), at room temperature, benzene reacts in 20-30 minutes, but methylbenzene only takes 1-2 minutes.

  +  H₂SO₄  == ==>    + H₂O

or

  +  SO₃  == ==>    

The yield with fuming sulfuric acid at 35^oC are shown in the table below.

The electrophile is actually sulfur trioxide (sulfur(VI) oxide, SO₃).

The theoretical percentage yields are quoted as if the methyl group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors - equal chance of electrophilic attack by SO₃.

What you see is the vast majority of the product involves substitution at the 2 and 4 positions of the benzene ring in methylbenzene. There is very little substitution at the 3 position.

This is due, as argued via the diagram above, because of the increased electron density at the 2, 4 and 6 benzene ring positions from the plus inductive effect of the methyl group of methylbenzene.

 

(c) Benzene ring chlorination of methylbenzene

  +  Cl₂  == FeCl₃ ==>      +  HCl

The reagents chlorine and iron(III)/aluminum chloride substitute a hydrogen atom with a chlorine atom in the benzene ring (NOT in the methyl group).

What you see is the vast majority of the product involves substitution at the 2 and 4 positions of the benzene ring in methylbenzene. There is only a trace of substitution on ring carbon 3.

This is due, as argued via the diagram above, because of the increased electron density at the 2, 4 and 6 ring positions from the plus inductive effect of the methyl group of methylbenzene.

The theoretical percentage yields are quoted as if the methyl group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors - equal chance of attack from the Cl⁺ electrophile.

See also Electrophilic substitution - ring halogenation of benzene/methylbenzene, properties & uses of aryl halides

(d) Benzene ring bromination of methylbenzene

Using bromine and iron(III) bromide you can substitute a hydrogen atom for a bromine atom in the benzene ring (NOT in the methyl group).

The theoretical percentage yields are quoted as if the methyl group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

What you see is the vast majority of the product involves substitution at the 2 and 4 positions of the benzene ring in methylbenzene and only trace of substitution at the 3 position.

This is due, as argued via the diagram above, because of the increased electron density at the 2, 4 and 6 ring positions from the plus inductive effect of the methyl group of methylbenzene.

See also Electrophilic substitution - ring halogenation of benzene/methylbenzene, properties & uses of aryl halides

(e) The nitration of phenol

The presence of the hydroxy group (OH) directly attached to the benzene ring( making the molecule a 'phenol', increase the electron density of the pi orbitals of the ring and greatly increases the reactivity of phenol towards electrophiles.

Phenol is so reactive, that even at low temperature (< 20^oC), with dilute nitric acid, electrophilic substitution readily takes place at the 2, 4 and 6 positions on the benzene rings.

The non-bonding electrons of the oxygen atom interact with the pi orbitals of the benzene ring - which outweighs any minus inductive effect from the more electronegative oxygen atom (electronegativities: C = 2.5, oxygen 3.5).

 

The theoretical percentage yields are quoted as if the hydroxy group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

What you see is the vast majority of the product involves substitution at the 2 and 4 positions of the benzene ring in phenol.

This is due, as argued via the diagram above, because of the increased electron density, specifically. at the 2, 4 and 6 ring positions from the inductive effect of the hydroxy group of phenol.

Another approach to explaining the extra reactivity at the 2, 4 and 6 positions of the benzene ring is to consider the three resonance structures of phenol, shown on the right of the diagram above.

You can draw structures that place a negative charge on carbon atoms 2, 4 and 6 of the ring, but not on ring carbons 3 and 5, where little substitution occurs with phenol.

Although the contribution of these three resonance structure is less than the first two, the effect is sufficient to promote much more substitution on the 2, 4 and 6 positions compared to 3 and 5.

The more negative the carbon atom, the more likely it is to allow the attacking electrophile to substitute the hydrogen atom.

 

With conc. nitric/sulfuric acids phenol gives 2,4,6-trinitrophenol (diagram above) - a very explosive product, but note the substitutions take place at the carbon atoms of highest electron density in the ring.

See also Electrophilic substitution - nitration of benzene and methylbenzene, properties and uses of nitro-aromatics

(f) Benzene ring bromination/chlorination of phenol

With excess chlorine water or bromine water room temperature, phenol gives an immediate white precipitate of 2,4,6-trichlorophenol or 2,4,6-tribromophenol, with almost zero substitution at the 3 and 5 positions of the benzene ring (structures in diagram below).

This further illustrates the much greater reactivity of phenol towards electrophiles compared to benzene itself/

See also Electrophilic substitution - ring halogenation of benzene/methylbenzene, properties & uses of aryl halides

(g) Electrophilic substitution of the benzene ring of an aromatic ether

The ether group, like the hydroxy group, increases the electron density of the benzene ring, particularly at the 2, 4 and 6 positions.

You can also, like with phenol, construct three resonance structures with a negative charge on benzene ring carbon atoms 2, 4 and 6.

Resonance structures for aromatic ethers e.g.

for methoxybenzene (R = CH₃), ethoxybenzene (R = CH₂CH₃)  and phenoxybenzene (R = C₆H₅)

So you would expect the 2nd substituent to go onto benzene ring carbons 2 or 4, and this is born out by the data below and comparable with phenol in terms of very little 3- substitution.

The theoretical percentage yields are quoted as if the RO- group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors in terms of electrophilic attack from the electrophiles NO₂⁺ or RC=O⁺.

The major products from methoxybenzene are:

e.g. from nitration: 2-methoxy-1-nitrobenzene  and  2-methoxy-1-nitrobenzene

7.14.3 The effect of a moderately deactivating group on substitution orientation in a monosubstituted benzene derivative - 2, 4 and 6 position directing groups (ortho and para substitution positions)

Certain groups, already present in a monosubstituted benzene derivative, can moderately decrease the electron density of the benzene ring and make the aromatic compound less reactive towards electrophiles.

These groups usually have just one electronegative atom e.g. a halogen atom that interacts with the pi orbitals of the benzene ring.

The electronegative substituent group results in a lowering of electron density, deactivating the benzene ring towards electrophiles, but deactivates more at the 3 and 5 positions so the 2, 4 and 6 positions are favoured by electrophilic substitution

(a) The nitration of chlorobenzene

  +  HNO₃  ===>         +  H₂O

The theoretical percentage yields are quoted as if the chloro group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

Chlorobenzene is less reactive than benzene, but, as you can see from the yield data, the deactivation is almost complete for the 3 position of the benzene ring (see the diagram below).

Although the overall electron density is reduced in the benzene ring of chlorobenzene, it is still the highest at ring carbons 2, 4 and 6, so those positions are more susceptible to electrophilic attack.

The 2nd diagram above, shows on the right, three resonance hybrids of chlorobenzene with a negative charge on carbon atoms 2, 4 and 6 on the benzene ring, favouring electrophilic attack by a positive electrophile, and less so on the 'neutral' carbon atoms 3 and 5.

See also Electrophilic substitution - nitration of benzene and methylbenzene, properties and uses of nitro-aromatics

(b) The nitration of bromobenzene

This is done by treating bromobenzene with a mixture of conc. nitric and sulfuric acids.

There is very little substitution at the 3 position of the benzene ring.

The theoretical percentage yields are quoted as if the bromo group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

The diagram below indicates the change in electron density around the benzene ring of bromobenzene caused by the bromine atom.

Although the overall electron density is reduced in the benzene ring of bromobenzene, it is still the highest at ring carbons 2, 4 and 6, so those positions are more susceptible to electrophilic attack.

The deactivation of the ring by the electronegative bromine atom, greatly affects the 3 position of the benzene ring, so the major products are bromo-2-chlorobenzene and bromo-4-chlorobenzene and the resonance hybrid structures contribute to the effect too.

The 2nd diagram above, shows on the right, three resonance hybrids of bromobenzene with a negative charge on carbon atoms 2, 4 and 6 on the benzene ring, favouring electrophilic attack by a positive electrophile, and less so on the 'neutral' carbon atoms 3 and 5.

See also Electrophilic substitution - nitration of benzene and methylbenzene, properties and uses of nitro-aromatics

 

(c) The ring chlorination of bromobenzene

This can be accomplished with chlorine and the halogen carrier catalyst aluminium chloride.

Although the overall electron density is reduced in the benzene ring of bromobenzene, it is still the highest at ring carbons 2, 4 and 6, so those positions are more susceptible to electrophilic attack from Cl⁺.

Again, the deactivation of the ring by the electronegative bromine atom, greatly affects the 3 position of the benzene ring, so the major products are bromo-2-chlorobenzene and bromo-4-chlorobenzene and the resonance hybrid structures contribute to the effect too.

See diagrams above for the nitration of bromobenzene to illustrate the orientation effect

See also Electrophilic substitution - ring halogenation of benzene/methylbenzene, properties & uses of aryl halides

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7.14.4 The effect of a deactivating group on substitution orientation of a monosubstituted benzene derivative - 3 and 5 position directing groups (meta substitution positions)

Certain groups, already present in a monosubstituted benzene derivative, can strongly decrease the electron density of the benzene ring and make the aromatic compound less reactive towards electrophiles.

These groups have at least one strongly electronegative atom and a double or triple bond that interacts with the pi orbitals of the benzene ring.

This results in a lowering of electron density, deactivating, but deactivates more at the 2, 4 and 6 positions so the 3 and 5 positions are more favoured by electrophilic attack and consequent substitution.

Examples of groups that considerably decrease reactivity, compared to benzene, by some means or other, are nitro -NO₂, carboxylic acid COOH, aldehyde -CHO, and sulfonic acid -SO₂OH

These favour electrophilic substitution at the 3 position (often > 70%) and their effect does fit in with them all being strongly electronegative groupings giving a -I inductive effect and/or theoretically, resonance hybrids with a positive charge on ring carbon atoms 2, 4 and 6.

These points are illustrated in the diagram below.

(a) The nitration of nitrobenzene

1,3-dinitrobenzene is the favoured substituent product when nitrobenzene is treated with a concentrated nitric acid and sulfuric acid mixture.

The theoretical percentage yields are quoted as if the nitro group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

The nitro O-N-O group is shown as delocalised system and merges with the pi bond system of the benzene ring, but it has, overall, an electron withdrawing effect, deactivating the ring.

 

On the right are three resonance structures of nitrobenzene with a positive charge on ring carbon atoms 2, 4 and 6 making them less favourable to attack from an incoming positive electrophile like NO₂+.

See also Electrophilic substitution - nitration of benzene and methylbenzene, properties and uses of nitro-aromatics

(b) The nitration of benzoic acid

The 3- substitution is highly favoured i.e. the major product is 3-nitrobenzoic acid.

The theoretical percentage yields are quoted as if the carboxylic acid group has no effect on the orientation of the product i.e. all 5 positions on the benzene ring have equal partial rate factors.

The >C=O delocalised and merges with the pi orbitals of the benzene ring, but the net effect is a large minus inductive effect, deactivating the ring, particularly at the 2, 4 and 6 positions.

 

See also Electrophilic substitution - nitration of benzene and methylbenzene, properties and uses of nitro-aromatics

Future additional work

Images for future work for meta directed substitution - add them plus note

Resonance structures for aromatic ketones R = CH₃, 1-phenylethanone , R = C₆H₅ diphenylmethanone

Resonance structures for benzenesulfonic acid

 

and implication of direction orientation for synthesis e.g. how to make 4-nitrobenzoic acid or 4-aminobenzoic acid

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