CSUMB
ESSP 311 Organic Chemistry I
Ronald W. Rinehart, Ph.D.

Chapter 12 Electrophilic Aromatic Substitution

     Chapter 12:  Reactions of Arenes.  Electrophilic Aromatic Substitution Reactions 

I.  Substitution vs Elimination
            A.  Kekule Structure of Benzene.
                        1.  Due to our representation of benzene one might expect benzene to undergo addition reactions.
                        2.  Addition is NOT observed.
                        3.  Substitution (of a hydrogen) occurs in order to retain aromaticity.

                        4.  Reaction referred to as Electrophilic Aromatic Substitution [EAS].
                                    a)  An electrophile attacks the electron-rich p-cloud of the ring. 

            B.  Mechanism
                        1.  The mechanisms of most electrophilic aromatic substitution reactions are very similar.
                        2.  Most mechanisms follow this basic three-step pattern:

II.  Reactions: 6 major types – learn the first 5!!
 

            A.  Nitration
                        1.  Overall reaction.

                         2.  Mechanism.

                   B.  Sulfonation
                        1.  Overall reaction.

                          2.  Mechanism.

                         3.  Sulfonic acids are strong acids, on the order of mineral acids such as HCl.
                                    a)  Arenesulfonic acids are completely dissociated in water.
                        4.  They tend to be highly water soluble.
                                    a)  This creates a problem in the isolation of the product.
                                    b)  Arenesulfonic acids are usually isolated as the sodium salt.
                                                i)  Even though the sodium salt is also water soluble, due to its lower solubility than NaCl or
                                                    Na₂SO₄, the product can be "salted out" by saturation of the aqueous solution with either salt.
                                                    [common ion effect]
                        5. Long-chain sodium alkylbenzenesulfonates are used as detergents and surfactants.
                                    a)  The sulfonate group is hydrophilic, the alkyl group is hydrophobic.
                                                The salt is "amphiphilic" or "amphipathic"
                                               
                                    b)  Amphiphilic compounds can be used to solubilize lipids (hydrophobic) in water or polar materials
                                                (hydrophilic) in organic (nonpolar) solvents through the formation of micelles.
                                    c)  An early detergent was produced by cationic polymerization of propene, forming a tetrameric
                                         alkene used to alkylate benzene, which was then sulfonated and converted to the sodium salt.
                                               

                                                 ii)  Problem: it biodegrades slowly due to the (unnatural) branched side chain.
                                                iii)  Widespread use created sewage treatment problems
                                    d)  Biodegradation problem solved by replacing branched-chain with C₁₂-C₁₅ straight chains         
                                                i)  Bacteria can rapidly biodegrade straight-chain alkyl groups.
                                                ii)  A formula of one type of modern household detergent is:

            C.  Halogenation.
                        1.  Overall reaction.

                         2.  X₂ = Cl₂, Br₂
                        3.  F₂ is too reactive; I₂ is too unreactive.
                        4.  Mechanism.

         D.  Friedel-Crafts Alkylation
                        1.  Overall reaction.

                        2.  R = 2^o, 3^o, -CH₃, -CH₂CH₃
                        3.  Primary alkyl groups other than Me or Et  rearrange.
                        4.  The reaction works with other reagents which generate a carbocation.                                     

 

                        5.  Mechanism.

                        6.  Complete the following equations:

                         7.  A limitation of Friedel-Crafts Alkylation: rings which are too deactivated will not react.
                                    a)  If an -NO₂ group is on the ring, no reaction will occur.
                                    b)  A ring with a single halogen atom will react, but any greater deactivation will result in no reaction.
                        8.  Try to synthesize n-propylbenzene.  What problem is encountered?
                                    Answer:  Rearrangement results in the formation of isopropylbenzene.

            E.  Friedel-Crafts Acylation
                        1.  Overall reaction.           

                         2.  This reaction works with acid (or acyl) chlorides or acid anhydrides.

                       


                        3.     An important feature of this reaction:  no rearrangements occur.   
                        4.  R = alkyl or aryl group.
                        5.  The mechanism involves the formation of the acylium ion (acyl cation).
                                    a)  stability of this ion (due to resonance stabilization) avoids rearrangement.

 

                        6.  Examples. 

                             7.  Mechanism.

                         8.  An excess of AlCl₃ must be used since the acylbenzene forms a complex with AlCl₃.

            F.  Synthesis of Alkylbenzenes via Acylation-Reduction
                        1.  Recall the problem encountered in the attempted synthesis of n-propylbenzene via Friedel-Crafts Alkylation.
                        2.  n-Alkylbenzenes can be synthesized by acylation followed by reduction:

                 c)  Reduction methods:  Both reduce aldehydes and ketones but not C=C, C≡C, RCO₂H

                                   



















      III.  Rate and Orientation in Electrophilic Aromatic Substitution.
            A.  Activation vs Deactivation of Benzene.
                        1.  Groups attached on the benzene ring can activate or deactivate benzene towards reaction.

                         2.  If a substituent "G" is electron-donating (either through inductive effects or resonance) then the
                                    ring is activated, since the cyclohexadienyl cationic intermediate is stabilized (and thus the transition
                                    state leading to the formation of the intermediate is also stabilized- Hammond's Postulate).

                                    a)  Groups which are activating are listed in Table 12.2.
                                                i)  Alkyl groups and groups which have N: or O:  directly attached to the ring are activating.
                                                ii)  They are also "ortho-para directing".
                        3.  Conversely, if the substituent is electron-withdrawing then the ring is deactivated:
                                    the rate of reaction decreases (relative to the unsubstituted benzene ring.)
                                    a)  Groups which are deactivating include the halogens (also o/p directing), -CF₃,
                                          and groups in which N or O are one atom removed from the ring. 
                                                i)  Except for the halogens, these groups are "meta directors."
            B.  The Effects of Substituents on Orientation of Substitution. Ortho/Para vs Meta Directors.
                        1.  In order to understand why -CH₃ is an ortho/para director we must look at the intermediates for
                                    ortho, para, and meta substitution.  (See Figure 12.7.)

                                    a)  The diagram above uses toluene and a generic electrophile but it could have used any alkyl group.
                                    b)  The mechanism of toluene attacking the electrophile at the various positions follows,
                                          showing the cyclohexadienyl intermediates.
                                                i)  Pay close attention to the position of the + charge and the methyl group when drawing the
                                                    various resonance structures.
                                                ii)  The methyl group stabilizes the cyclohexadienyl intermediates via the inductive effect.
                                                iii)  ALL activating groups are ortho/para directors.            
                                    c)  Groups with N: or O: directly attached to the ring stabilize intermediates via resonance effects.
                                                i)  These effects are more important than the electron-withdrawing inductive effects of N and O

                        2.  To understand why -CF₃ is a meta director, look at intermediates for ortho, para, and meta substitution.                                      (See Figure 12.8).

                                    a)  Consider the mechanism of (trifluoromethyl)benzene  attacking the E⁺ at the various positions:

                                                 i)  -CF₃ destabilizes the cyclohexadienyl intermediates via the inductive effect;
                                                            this effect is least in the meta-substituted case.
                                                ii)  All deactivating groups (except the halogens) are meta directors.
                                                iii)  Any group in which the atom DIRECTLY attached to the ring has a positive polarity is
                                                            deactivating

                        3.  Halogens are a special case since they are deactivating groups yet are ortho/para directors.
                                    a)  They are deactivating due to their high electronegativities (inductive effects).
                                    b)  They are ortho/para directors since they can, via their lone pairs, donate electrons into
                                         the pi system of the ring when substitution is o/p (resonance effect):
 

                         4.  Multiple Substituent Effects.
                                    a)  When two or more substituents are on the ring the reactivity and orientation of further substitution
                                                is determined by the cumulative effects of the substituents.
                                    b)  The effects of substituents can be reinforcing:

                                   






                                    c)  When two groups oppose each other in directing, the more activating substituent controls regioselectivity:

                                   






                                    d)  When two alkyl groups are on the ring substitution occurs at the less hindered site:

                                   






















                                    e)  When an alkyl group and a halogen atom are attached to the ring it is difficult to
                                         predict where substitution will occur due to their weak directing abilities.
                        5.  Synthesis of disubstituted and other multisubstituted benzenes must take into account the order
                                    in which substituent groups are introduced to the ring. 
                                    a)   If you want a meta-substituted product you must first attach a meta director.
                                    b)  You cannot run Friedel-Crafts reactions on nitrated rings.
                                    c)  If possible put activating groups on before deactivating groups in order to         increase product yield.
                                                (e.g., alkylate prior to halogenation.)
                        6.  Synthesize the following compounds starting   with benzene:

                        7.  Substitution in naphthalene:
                                    a)  Polycyclic aromatic hydrocarbons undergo electrophilic aromatic substitution
                                                with the same reagents as for benzene.
                                    b)  Polycyclic aromatic hydrocarbons are generally more reactive than benzene.
                                    c)  With more than one ring, even monosubstitution results in a mixture of products.
                                    d)  Naphthalene only has two sites of monosubstitution, C-1 and C-2.
                                                i)  C-1 is favored since the arenium ion formed in this case is stabilized via allylic resonance
                                                    without sacrificing benzenoid character in the other ring.

                        7.  Substitution can occur in heterocyclic aromatic compounds.
                                    a)  Pyridine acts as a deactivated ring due to the high electronegativity of N which results in the pi
                                                electrons of the ring more tightly held.
                                                i)  In reaction conditions with acids the pyridine molecule becomes protonated, forming the
                                                            even less reactive pyridinium ion.
                                                ii)  Lewis acid catalysts (AlCl₃, FeX₃) bond to N which further deactivates the ring.
                                                iii)  When EAS does occur, it occurs at C-3 (N is atom #1).

                                    b)  Pyrrole, furan, and thiophene: extremely reactive toward EAS (on the order of  phenol).

                                                i)  These compounds have 6 pi electrons but they are spread over 5 atoms (vs six in benzene)
                                                            and are less tightly held than in benzene.
                                                ii)  Electrophilic attack is favored at C-2 rather than C-3 since at C-2 there are three resonance
                                                            structures which can be drawn for the intermediate vs two for attack at C-3:

 Many thanks to Rod Oka of MPC for generously sharing his "Lecture Companion" outline,
reproduced here in extensively modified form by permission, with web references and other goodies added by me.
Structures drawn with  CS ChemOffice ChemDraw™, MDL IsisDraw™ and ACD Labs ChemSketch™ .