Chemistry of Benzene Substituents: Alkylbenzenes, Phenols and Benzenamines

Reactivity at the Phenylmethyl (Benzyl) Carbon: Benzylic Resonance Stabilization

The methyl C-H bonds in methylbenzene are relatively weak with respect to homolytic and heterolytic cleavage. The phenylmethyl (benzyl) group may be viewed as a benzene ring whose system overlaps with an extra p orbital on the attached alkyl carbon:

Reactivity at the Phenylmethyl (Benzyl) Carbon: Benzylic Resonance Stabilization

Benzylic radicals are reactive intermediates in the halogenation of alkylbenzenes. Benzene will not react with Cl2 or Br2 unless a Lewis acid is added:

Heat or light allows attack of Cl2 or Br2 on methylbenzene even in the absence of a catalyst, however, attack is at the methyl group, not the aromatic ring. Excess halogen leads to multiple substitution.

The mechanism of benzylic halogenation proceeds through radical intermediates:

The benzylic C-H bond is relatively weak (DHo=87 kcal mol-1) due to resonance stabilization of the intermediate radical formed.

Subsequent halogen attack is always at the benzylic position because attack at an aromatic carbon would destroy the aromatic character of the ring.

Benzylic cations delocalize the positive charge.

Benzylic resonance can strongly affect the reactivity of benzylic halides and sulfonates in nucleophilic displacements. For example, a primary benzylic tosylate rapidly reacts with ethanol via an SN1 reaction:

Delocalization of positive charge into the aromatic ring facilitates the dissociation of the starting sulfonate:

Several benzylic cations are stable enough to have been isolated. The X-ray structure of 2-phenyl-2-propyl cation (as its SbF6- salt) was obtained in 1997.

A para methoxy substituent on the benzene ring allows for extra stabilization of the benzylic positive charge. In its absence, the SN2 reaction may dominate due to the lack of steric interference and the stabilization of the SN2 transition state by overlap with the benzene system.

Resonance in benzylic anions makes benzylic hydrogens relatively acidic.

The anion, radical and cation adjacent to a benzene ring are all stabilized by conjugation:

The acidity of methylbenzene (pKa~41) is considerably greater than that of ethane (pKa~50) and comparable to that of propene (pKa~40) which can be deprotonated to form the resonance-stabilized 2-propenyl anion. Consequently, methylbenzene can be deprotonated by butyllithium to generate phenylmethyllithium:

Benzylic Oxidations and Reductions

Oxidation of alkyl-substituted benzenes leads to aromatic ketones and acids.
Hot KMnO4 and Na2Cr2O7 may oxidize alkylbenzenes all the way to benzoic acids. These reactions require at least one benzylic C-H bond to be present in the starting materials (tertiary alkylbenzenes are inert).

The oxidation reaction proceeds through the alcohol, the ketone and then the acid. It can be stopped at the ketone stage under milder conditions.

Benzylic alcohols, in the presence of other non-benzylic hydroxy groups, can be oxidized to the corresponding carbonyl compounds under mild conditions.

Benzylic ethers are cleaved by hydrogenolysis.

Exposure of benzylic alcohols or ethers to hydrogen in the presence of a metal catalyst leads to cleavage of a -bond by catalytically activated hydrogen.

Since hydrogenolysis is not possible for ordinary alcohols and ethers, the phenylmethyl substituent is a valuable protecting group for hydroxy functions.

Protection by a tertiary butyl group would require acid to cleave, which might cause dehydration.

Names and Properties of Phenols

In hydroxy-substituted arenes (phenols), the system of the benzene ring overlaps an occupied p orbital on the oxygen atom. This results in delocalization similar to that found in benzylic anions.

Enols are usually unstable and revert to their ketone forms. Phenols, however prefer the enol form which preserves the aromatic nature of the aromatic ring.

Names and Properties of Phenols

Phenols are hydroxyarenes.
Phenol was formerly known as carbolic acid. Aqueous solutions of phenol (or its derivatives) are used as disinfectants. Its main use is in the preparation of polymers (phenolic resins). Pure phenol is toxic and causes severe skin burns.

Substituted phenols are named as phenols, benzenediols or benzenetriols. Some common names are accepted by IUPAC. Substituted phenols find uses in photography, dyeing and tanning. Bisphenol A is an important monomer in the synthesis of epoxyresins and polycarbonates.

Phenols containing a carboxylic acid functionality (higher ranking) are called hydroxybenzoic acids. Phenyl ethers are named as alkoxybenzenes. As a substituent, C6H5O is called phenoxy.

Examples of phenols possessing physiological activity are:

Phenols are unusually acidic.

The pKa values of phenols range from 8 to 10. They are less acidic than carboxylic acids (pKa=4-5) and stronger than alkanols (pKa=16-18). The acidic nature of phenols is due to resonance stabilization of the phenoxide ion:

Substituents can affect the acidity of phenols:

Multiple nitrations can increase the acidity to that of carboxylic or even mineral acids. Electron donating substituents have the opposite effect:

Preparation of Phenols: Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution may follow an additionelimination pathway.
Displacement of a group (other than hydrogen) from an aromatic ring is called ipso substitution.

The transformation is called nucleophilic aromatic substitution. Success of this reaction is dependent upon the presence of one or stronger electron-withdrawing groups located on the ring ortho or para to the leaving group. Electron-withdrawing groups stabilize the intermediate anion by resonance.

Nucleophilic aromatic substitution reactions proceed by a two-step addition-elimination sequence.

In the meta compound, 1-chloro-3,5-dinitrobenzene, ipso substitution does not occur:

The reactivity of haloarenes in nucleophilic substitutions increases with the nucleophilicity of the reagent and the number of electron-withdrawing groups on the ring.

Haloarenes may react through benzyne intermediates.

Haloarenes without electron-withdrawing substituents can undergo nucleophilic substitution at highly elevated temperatures and pressures.

When radioactive chlorobenzene is reacted with KNH2, as in the previous reaction, a curious result is obtained:

The mechanism of this reaction involves the base-induced elimination of HX from the benzene ring to give alkynes.

Both reactions of Step 1 are difficult:

The acidity of the phenyl C-H bond is very low. The resulting negative charge upon deprotonation cannot be resonance-stabilized since the sp2 orbital is perpendicular to the aromatic frame. The resulting benzyne intermediate is very highly strained.

Benzyne is a strained cycloalkyne.

Benzyne can be observed spectroscopically under special conditions but is too unstable to be isolated. It can be observed in the IR and UV spectra of benzocyclobutenedione, which has undergone photolysis in frozen argon.

The triple bond in benzyne exhibits an IR-stretching frequency of 1846 cm1, intermediate between that of a normal double bond (~1652 cm-1) and a normal triple bond (~2207 cm-1). The 13C NMR spectra for the benzyne carbons occurs at = 182.7 ppm, also atypical of pure triple bonds. The bond is weakened by poor p-orbital overlap in the plane of the ring.

Phenols are produced from arenediazonium salts.

The usual laboratory procedure for synthesizing phenols is through arenediazonium salts, ArN2+X-. Primary benzenamines (anilines) are attacked by cold nitrous to give relatively stable arenediazonium salts in a reaction called diazotization.

When arenediazonium ions are heated, nitrogen is evolved and reactive aryl cations are produced, which are then trapped by water to form phenols.

Alcohol Chemistry of Phenols

The oxygen in phenols is only weakly basic.
Phenols can be protonated by strong acids to give phenyloxonium ions. The pKas for phenyloxonium ions are lower than those of alkyloxonium ions, however, because the oxygen lone electron pairs are delocalized into the benzene ring.

Phenyloxonium derivatives do not dissociate to form phenyl cations: The energy of such ions is too high. Protonation of alkoxybenzenes, however, allows the bond between the oxygen and the alkyl group to be readily cleaved in the presence of nucleophiles such as Br- or I-.

Alkoxybenzenes are prepared by Williamson ether synthesis.

Many alkoxybenzenes can be prepared using the Williamson ether synthesis since the phenoxide ions obtained by deprotonation of phenols are good nucleophiles. Phenoxides can displace the leaving groups from haloalkanes and alkyl sulfonates.

Esterification leads to phenyl alkanoates.

Esterification of carboxylic acids with phenols requires an activated carboxylic acid derivative such as an alkanoyl halide or a carboxylic anhydride.

Electrophilic Substitution of Phenols

The OH group in a phenol strongly activates the ortho and para position towards electrophilic substitution. Dilute nitric acid causes nitration:

Friedel-Crafts alkanoylation of a phenol is better carried on an ether derivative of the phenol to avoid ester formation:

Halogenation of phenols occurs readily and a catalyst is not required. Multiple halogenations are frequently observed but can be controlled by using a lower temperature and a less polar solvent.

Para electrophilic attack frequently dominates because of steric effects. The ratio of para to ortho products is highly dependent upon reagents and reaction conditions.

Under basic conditions, phenols can undergo electrophilic substitution through intermediate phenoxide ions, even with very mild electrophiles.

The initial aldol products are unstable and dehydrate upon heating, giving reactive intermediates called quinomethanes.

Quinomethanes are ,-unsaturated carbonyl compounds, which can undergo Michael additions with excess phenoxide ion. Subsequent repeated hydroxymethylation and Michael addition eventually leads to the formation of a complex phenol-formaldehyde copolymer called a phenolic resin.

The precursor to asprin, o-hydroxybenzoic acid, can be prepared via the Kolbe reaction:

An Electrocyclic Reaction of the Benzene Ring: The Claisen Rearrangement

The Claisen rearrangement is a concerted reaction with a transition state that accommodates the movement of six electrons.

With the non-aromatic 1-ethenyloxy-2-propene system, the rearrangement stops at the carbonyl stage because there is no driving force for enolization. This is called the aliphatic Claisen rearrangement.

The carbon analog of the Claisen rearrangement takes place in compounds containing 1,5-diene units. It is called the Cope rearrangement:

All of the preceding rearrangements are related to electrocyclic reactions that interconvert cis-1,3,5-hexatriene with 1,3-cyclohexadiene.

The only difference is the absence of a double bond connecting the terminal bonds.

Oxidation of Phenols: Cyclohexadienediones (Benzoquinones)

Cyclohexadienediones (benzoquinones) and benzenediols (hydroquinones and catechols) are redox couples.
The phenols 1,2- and 1,4-benzenediol are oxidized to their corresponding diketones by oxidizing agents such as sodium dichromate or silver oxide.

When the resulting diones are reactive, as for o-benzoquinone, yields may be variable. The mechanism or the redox process that interconverts hydroquinone and pbenzoquinone passes through a radical intermediate:

Redox processes similar to this occur widely in nature.

The enone units in 2,5-cyclohexadiene-1,4-diones (pbenzoquinones) undergo conjugate and Diels-Alder additions.
p-Benzoquinones function as reactive ,-unsaturated ketones in conjugate addition reactions:

The double bonds in ,-unsaturated ketones also undergo cycloadditions to dienes:

Oxidation-Reduction Processes in Nature

Ubiquinones mediate the biological reduction of oxygen to water.
Nature utilizes the benzoquinone-hydroquinone redox couple in the reversible oxidation reactions of the cascade of steps by which molecular oxygen is used in biochemical degradations. The ubiquinones, collectively called coenzyme Q, CoQ or Q, are an important series of compounds used for this purpose.

An enzyme system that utilized NADH, a biological reductant, converts Q into its reduced form, QH2. QH2 then participates in a series of reactions involving the cytochromes (electron-transporting iron containing proteins) and ending with the reduction of O2 to water:

Phenol derivatives protect cell membranes from oxidative damage.

Two intermediates in the conversion of molecular oxygen into water are the highly reactive radicals superoxide, O2-, and the hydroxyl radical, OH, which arises from the cleavage of H2O2. An example of the damage caused by reactive radicals is illustrated by the reaction with a phosphoglyceride containing an unsaturated fatty acid:

Cleavage of the relatively weak O-O bond gives rise to an alkoxy radical which may decompose (-scission) to an unsaturated aldehyde.

Related, but more complex mechanisms, yield unsaturated hydroxyaldehydes, such as trans-4-hydroxy-2-nonenal and propanedial.

Both propanedial and the ,-unsaturated aldehydes are extremely toxic because they are capable of cross-linking nucleophilic amino and mercapto groups from two different parts of one protein molecule, or from two different protein molecules.

Naturally occurring antioxidant systems defend lipid molecules inside cell membranes from oxidative destruction. The most important of these is vitamin E, a reducing agent possessing a long hydrocarbon chain, which makes it lipid-soluble. Vitamin E functions by its ability to break the propagation chain of lipid oxidation by the reduction of radical species.

The vitamin-E radical formed is relatively unreactive because of extensive delocalization of the electron and the steric hindrance of the methyl substituents. Vitamin E is regenerated at the membrane surface by water-soluble reducing agents such as vitamin c.

The semidehydroascorbic acid decomposes to lower MW water-soluble compounds, which are excreted by the body.

Benzoquinones consume glutathione, an intracellular reducing agent.

Glutathione is a small peptide that incorporates a mercapto functional group. The mercapto group serves to reduce disulfide linkages in proteins to SH groups and to maintain the iron in hemoglobin in the +2 state.

Glutathione also is involved in the reduction of oxidants, such as H2O2, which may be present in the cell:

Extensive glutathione depletion may result in cell death. Benzoquinones and related compounds react irreversibly with glutathione in the liver by conjugate addition. Very high doses of acetaminophen exhibits such toxicity:

Synthetic analogs of vitamin E are preservatives.

Several food additives function as antioxidants: BHA and BHT.

Addition of BHA to butter increases its storage life from months to years. Both BHA and BHT function like vitamin E, reducing oxygen radicals and interrupting the propagation of oxidative processes.

Arenediazonium Salts
Arenediazonium salts are stabilized by resonance.
The stability of arenediazonium salts, relative to similar alkane salts, is due to resonance and the high energy of the aryl cation formed if N2 were to be lost.

At temperatures greater than 50oC, nitrogen is lost to form the very reactive phenyl cation, which forms phenols in aqueous solutions.

The phenyl cation is reactive for several reasons. The positive charge on the phenyl cation cannot be resonancestabilized. The empty orbital associated with the positive charge is perpendicular to the framework of the benzene ring.

Also, the cationic carbon would prefer sp hybridization which is precluded by the rigid frame of the benzene ring.

Arenediazonium salts can be converted into other substituted benzenes.

Decomposition of arenediazoniuim salts in the presence of nucleophiles other than water, leads to the corresponding substituted benzenes:

Reactions with other halides often are complicated by side reactions. To alleviate this problem, the Sandmeyer reaction may be employed, which relies on the facilitation of the reaction by cuprous salts.

The diazonium group can be removed by reducing agents. The amino group in arenamines can be replaced by hydrogen by the sequence: diazotization-reduction. The reducing agent used is aqueous hypophosphorous acid, H3PO2. This method is useful for removing an amino group originally introduced as a directing substituent in electrophilic aromatic substitution.

Diazotization can be used in the synthetic strategy for 1,3dibromobenzene. If direct bromination is used, the second bromine atom will be introduced at the ortho or para position.

Electrophilic Substitution with Arenediazonium Salts: Diazo Coupling

Arenediazonium ions are electrophilic (they are positively charged), although not very reactive in electrophilic aromatic substitution reactions. When the substrate is an activated arene, however, such as phenol or benzenamine, arenediazonium ions can undergo electrophilic aromatic substitution.

This reaction is called diazo coupling, and it leads to highly colored compounds called azo dyes.

Azo dyes used in the clothing industry usually contain sulfonic acid groups to impart water solubility and to allow the dye molecule to ionically attach itself to the textile polymer framework.

Important Concepts
1.

Resonance Stabilization benzylic radicals,

cations and anions are stabilized by resonance of the resulting centers with a benzene system.
2.

Nucleophilic Aromatic Ipso Substitution

3.

4.

5.

accelerates with: Nucleophilicity of the attacking species Number of electron-withdrawing groups on the ring (especially if ortho or para, to point of attack) Benzyne destabilized by strain at the sp-hybridized carbons in the triple bond Phenols aromatic enols (undergoing reactions typical of the hydroxy group and the aromatic ring) Cyclohexadienediones and benzenediols function as redox couples.

Important Concepts
6.

Vitamin E and the highly substituted phenol

7.

8.

derivatives BHA and BHT inhibit radical-chain oxidation of lipids. Vitamin C (antioxidant) is capable of regenerating vitamin E at cell membrane surfaces. Arenediazonium Ions furnish reactive aryl cations with a positive charge that cannot be delocalized into the aromatic ring. Electrophilic Aromatic Substitution the amino group can be used to direct electrophilic aromatic substitution, after which it can be replaced by diazotization and substitution, including reduction.