Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

1

How Some Substituents on a Benzene Ring Can Be Chemically Changed a) Benzylic Halogenation with NBS A benzylic hydrogen can be replaced with a halogen by radical substitution reactions described in Chapter 12 (p.484-487).

or hX = Cl or Br

X2

XH

or h

NBSBrH

b) Conversion of Alkyl Groups or Benzylic Alcohols to Carboxyl Groups with Cr+6 or Mn+7 Reagents

Methyl, primary alkyl, and secondary alkyl groups are converted to carboxyl (CO2H) groups by Cr+6 and Mn+7 oxidizing agents.

MeR RR

or or

Mn+7 or Cr+6

reagent

CO2H

KMnO4 and H+, Na2Cr2O7 are commonly used oxidizing agents The first step in these oxidation reactions is the removal of a benzylic hydrogen, so tertiary alkyl groups are unaffected by Cr+6 and Mn+7 oxidizing agents.

RRMn+7 or Cr+6

reagent

R

NOREACTION

tertiary alkyl group

The same reagents will oxidize benzylic alcohols to benzoic acids.

OH OHR

or or

Mn+7 or Cr+6

reagent

CO2HOH R R

c) Oxidation of Benzylic Alcohols to Ketones or Aldehydes with MnO2

OH

MnO2

H OHH OH

MnO2

R ORH

1° benzylalcohol

aldehyde 2° benzylalcohol

ketone

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

2

d) Reduction of Nitro Groups to Amino Groups A nitro substituent can be reduced to an amino substituent. Either a metal (tin, iron, or zinc) pul an acid (HCl) or catalytic hydrogenation can be used to carry out this reaction.

NO2 NH21. Sn, HCl

Pd/CH2

2. NaOH

Electrophilic Aromatic Substitution Reactions of Substituted Benzenes Like benzene, substituted benzenes undergo the same five electrophilic aromatic substitution reactions we discussed in Chapter15.

Activating/Deactivating Effects of Substituents (Reactivity)

Relative Rates of Electrophilic Substitution Recall from Chapter 15 that electrophilic aromatic substitution takes place by a two step mechanism that proceeds through a resonance delocalized carbocation intermediate:

It is the stability of the carbocation intermediate, formed in the first step, which determines the overall rate of the reaction. (Technically, it’s the stability of the transition state leading to the

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

3

carbocation, but its stability directly parallels that of the carbocation.) Consequently, replacing one of the hydrogen atoms on the benzene ring with an electron-donating group increases the rate of the reaction. Replacing it with an electron-withdrawing group decreases the rate of the reaction.

Substituents that increase the rate of the electrophilic aromatic substitution reaction are known as activating substituents. Those that decrease the rate are known as deactivating substituents. We will see later that the regioselectivity of electrophilic aromatic substitution reactions is also governed by the electron-donating and electron-withdrawing properties of the substituents attached to the benzene ring. Hyperconjugative Electron Donation We’ve seen previously (initially in Chapter 4) that alkyl substituents (e.g., Me, Et, etc.) stabilize carbocations through their ability to donate electron density to the electron-deficient, positively charged carbon center through a process known as hyperconjugation. (Remember 3° > 2° > 1° for SN1 reactions? This is where that rule comes from.) Thus alkyl groups are more electron donating than hydrogen, and alkyl substitution on a benzene ring increases the rate of electrophilic aromatic substitution. In other words, alkyl groups are activating substituents.

Inductive Electron Withdrawal We’ve seen previously (initially in Chapter 1) that replacing one of the hydrogen atoms in a molecule with an electronegative element leads to decreased electron density in the rest of the molecule through a process known as inductive electron withdrawal. In inductive electron withdrawal, electrons are pulled toward the electronegative atom through the bonds of the molecule. (Inductive electron withdrawal explains, for example, why F–CH2–CO2H is a stronger acid than H–CH2–CO2H.) The +NH3 group is an example of a substituent with withdraws electrons inductively because it is more electronegative than hydrogen, and +NH3 substitution on a benzene ring decreases the rate of electrophilic aromatic substitution. In other words, +NH3 groups are deactivating substituents.

Resonance Electron Donation If a substituent has a lone pair on the atom directly attached to the benzene ring, the lone pair can be delocalized into the ring. This is known as resonance electron donation, which we first discussed in Chapter 7. Hydroxy (OH), alkoxy (OR) and amino (NH2, NHR, NR2) substituents

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

4

donate electron density by resonance. These substituents also withdraw electrons inductively because the atom attached to the benzene ring is more electronegative than hydrogen. However more electron density is donated to the system by lone pair donation (resonance delocalization) than is drawn away through bonds (inductive electron withdrawal). Thus hydroxy, alkoxy and amino groups are more electron donating than hydrogen, and substitution of one of these groups onto a benzene ring increases the rate of electrophilic aromatic substitution. In other words, hydroxyl, alkoxy and amino groups groups are activating substituents.

Halogen (F, Cl, Br, and I) substituents also donate electron density by resonance and remove electron density by inductive withdrawal. In the case of halogen substitution, inductive electron withdrawal is the dominant effect, and halogen atoms are deactivating substituents.

Resonance Electron Withdrawal If a substituent is attached to the benzene ring by an atom by an atom that is doubly or triply bonded to a more electronegative atom, the electrons or the ring can be delocalized onto that substituent. This is known as resonance electron withdrawal, which we first discussed in Chapter 7.

Relative Reactivity of Substituted Benzenes The table on the following page lists substituents according to their ability to activate or deactivate a benzene ring toward electrophilic aromatic substitution. Strongly activating and moderately activating substituents are characterized by resonance electron donation from a nitrogen or oxygen atom. The difference between these substituents is that there is an electron-withdrawing carbonyl group attached to the lone pair donating nitrogen or oxygen atom in the moderately activating substituents. The carbonyl group competes with the benzene ring for the lone pair leading to diminished electron donation to the benzene ring.

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

5

NH2

NHR

NR2

OH

OR

stronglyactivating

HN moderately

activatingCRO

O CRO

R

Ar weaklyactivating

CH CHR

Cl

Br

I

weaklydeactivating

H

moderatelydeactivating

CRO

CXO

C

stronglydeactivating

N

SO3H

NH3

NO2

NR3

mostactivating

mostdeactivating

ortho/paradirecting

metadirecting

Standard of comparison

Activating substituents

Deactivating substituents

F

REACTIVITY SELECTIVITY

Weakly activating substituents are comprised of alkyl, aryl and alkenyl groups. Alkyl groups donate -bonding electrons through hyperconjugation. Aryl and alkenyl groups donate -bonding electrons by resonance. Weakly deactivating substituents are comprised of the halogens. Halogen lone pairs donate electron density by resonance. However, they are more weakly donating the nitrogen and oxygen lone pairs of activating substituents. Fluorine is more weakly donating because of its high electronegativity. The other halogens are more weakly donating because of their size which greatly diminishes their ability to form bonds. As a result inductive electron withdrawal is greater than resonance electron donation for the halogens. Moderately deactivating substituents all have a carbonyl group directly attached to the benzene ring.

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

6

Strongly deactivating substituents include the nitrile group (C N) and a group of others that are directly attached to the benzene ring by an electronegative atom which has one or both of the following characteristics:

a full positive charge is doubly or triply bonded to a more electronegative atom

Directing Effects of Substituents (Selectivity) We have two possible scenarios:

NMe2 OMe Me Cl

favor ortho & parasubstitution

-NMe2, -OMe, -Me, and -Cl are said to be

ortho/para (o/p) directing

NO2 SO3H CN

favor metasubstitution

-NO2, , -SO3H, and -CN are said to be

meta directing

RO

CO

R

The directing effects of electron-donating (EDG) or electron-withdrawing (EWG) substituents can readily be seen by considering the effect of these groups on the benzene system to which they are attached:

EDG

ortho/para (o/p) directing--

-

ortho and para positionsare more electron-rich

EWG++

+

ortho and para positionsare more electron-deficient

meta directing

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

7

A more detailed explanation of directing effects comes from examining the influence of electron-donating or electron-withdrawing substituents on the resonance-delocalized, carbocation intermediates formed during the course of the electrophilic aromatic substitution reaction:

X

+ E+

X

X

X

HE

HE

H E

X

X

X

HE

HE

H E

X

X

X

HE

HE

H E

ortho

para

meta

Only ortho and para substitution delocalize positive charge to the carbon bearing the electron-donating or electron-withdrawing substituent. The key resonance structures are highlighted. When the substituent (X) is electron-donating the cationic intermediate is stabilized when substitution occurs ortho or para while no such stabilization is possible for meta substitution. When the substituent (X) is electron-withdrawing the cationic intermediate is destabilized when substitution occurs ortho or para while no such destabilization occurs for meta substitution. Thus, we have:

Carbocation-stabilizing substituents stabilize the ortho and para substitution pathways and are therefore ortho/para directing.

Carbocation-destabilizing substituents destabilize the ortho and para substitution pathways and are therefore meta directing.

Note that we reach the same conclusion we did with the + and - symbols, just a more detailed explanation.

Specific Examples

All reactions show preference for ortho and para products, but the ortho/para ratio varies a bit from reaction to reaction. Note that the highest para selectivity is observed for the largest electrophile.

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

8

For the nitration reaction the ortho/para ratio is 1.6/1. If we factor out the intrinsic statistical preference for ortho (2/1), we see that the para position is just slightly more reactive. Compared to the other substitution reactions, the electrophile in the nitration reaction (NO2

+) is smaller and much more reactive. Therefore it makes sense that it would be less discriminating towards the differences (mainly steric) between the ortho and para positions than larger, slower reacting electrophiles.

Both reactions show preference for meta substitution, but they differ in selectivity. Selectivity logically correlates with the electron-withdrawing ability of the substituent with the more electron-withdrawing nitro group imparting higher meta selectivity. The Ortho-Para Ratio Ortho substitution has a 2:1 statistical advantage, but a steric disadvantage. For reactions involving small electrophiles (like NO2

+) and small substituents (like methyl), the ortho product will predominate.

CH3

H2SO4

HNO3

CH3NO2

CH3

NO2

39%61%

+

Replacing the methyl substituent with a t-butyl group leads to a reaction where the para product is favored.

Larger electrophiles also lead to higher para selectivity, as we’ve already seen.

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

9

Other Substituent Effects Methoxy and hydroxy substituents are so strongly activating that halogenation is carried out without the Lewis acid catalyst.

In the presence of a Lewis acid catalyst, the tribromide is obtained.

Friedel-Crafts reactions FAIL with moderately or strongly deactivated benzene rings.

SO3H

AlCl3NO REACTION

Cl

NO2

AlCl3NO REACTION

Cl

O

Since Friedel-Crafts reactions are the slowest of the electrophilic aromatic substitution reactions they require a more nucleophilic benzene ring. Anilines (amino-substituted benzenes) also FAIL to undergo Friedel-Crafts reactions.

Coordination of the nitrogen lone pair to the Lewis acid converts the amino group to a strongly deactivating substituent. Less basic hydroxy and methoxy substituents do NOT complex with the Lewis acid, so:

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

10

Polysubstitution Multiple substituents can have competing of reinforcing effects on selectivity.

Reinforcing

Competing

Arenediazonium Salts Nucleophilic substitution reactions of diazonium salts occur readily because the leaving group is a molecule of nitrogen gas.

Diazonium salts are easily prepared by treatment of anilines with nitrous acid (HNO2). Since HNO2 is too unstable to safely store, it is generated in the presence of the aniline substrate (formed in situ) by treatment of NaNO2 with a strong acid.

NH2

NaNO2, HCl

NN

Cl�–

0 ºC

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

11

Mechanism of Diazonium Ion Formation Sandmeyer Reactions Diazonium salts undergo nucleophilic substitution reactions with Cu+ salts of Br–, Cl –, or CN– anions. Collectively these are known as Sandmeyer reactions.

Other Halide Substitution Reactions Although copper(I) salts are used (and required) for chloro and bromo substitution reactions, iodo and fluoro substition reactions employ different conditions. Potassium iodide is used for iodo substitution:

HBF4 is the fluoride source for the fluoro substitution:

This is known as the Schiemann reaction.

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

12

Formation of Phenols (Hydroxide Substitution) Heating an acidic aqueous solution of a diazonium salt will convert it to the corresponding phenol (an OH substitution reaction where H2O is the nucleophile).

Alternatively, a phenol can be formed (usually in higher yield) by treatment of the diazonium salt with an aqueous solution of Cu2O and Cu(NO3)2.

Replacing the Diazonium Group with a Hydrogen Atom Treatment of a diazonium salt with hypophosphorous acid leads to replacement of the diazonium group with a hydrogen atom.

Of course, this looks pretty useless if the diazonium group is the only thing attached to your benzene ring. However, this can be a very useful transformation for removal of an amino group from a more highly substituted benzene. For example, 1,3,5-tribromobenzene can be synthesized by the following sequence of reactions.

Note that direct bromination of benzene could never lead to this isomer due to the ortho/para directing effect of the bromo substituent.

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

13

Nucleophilic Aromatic Substitution We learned earlier that SN2 reactions do not occur at sp2 centers, so the failure of halobenzenes to undergo nucleophilic substitution should come as no surprise.

However,

Some relative rates:

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

14

Mechanism of the Nucleophilic Aromatic Substitution (SNAr) Reaction Nucleophilic aromatic substitution proceeds through a stepwise, addition-elimination mechanism involving a resonance delocalized anionic intermediate. The reaction only occurs if there is a sufficiently powerful electron-withdrawing group positioned either ortho or para to the leaving group, where it can help to further delocalize (and stabilize) the negative charge.

Note that placement of the electron-withdrawing group meta to the leaving group is ineffective at promoting nucleophilic aromatic substitution because the negative charge of the anionic intermediate is not delocalized to the meta positions. Substitution via the Benzyne Intermediate We have learned that simple halobenzenes fail to undergo nucleophilic substitution by an SN2 (or SN1) mechanism and that nitro-substituted halobenzenes can undergo substitution via the SNAr mechanism (addition-elimination) only if the nitro group is appropriately positioned ortho or para to the leaving group. Given all this, how can we account for the following substitution reaction which seems to contradict everything we have said so far?

A clue to the mechanism of the reaction comes from the following isotopic labeling experiment.

This result suggests that the product is formed from a symmetrical intermediate which is equally reactive at the isotopically labeled position and the carbon adjacent to it:

Chem 2261 Notes Chemistry of Benzene and Its Derivatives (Bruice, Chapter 16)

15

A stepwise elimination-addition mechanism