AROMATIC SUBSTITUTION REACTIONS REACTIONS

NOMENCLATURE

methylbenzene 1-chloro-3-methylbenzene (toluene) 1-bromo-3-nitrobenzene 1,4-dimethylbenzene

SOME SPECIAL NAMES tolueneanilineanisole o-xylenem-xylene p-xylene phenol benzoic acid

ortho meta para ortho, meta and para Positions m-nitrotoluene 3-nitrotoluene 1-methyl-3-nitrobenzene o- m- p p-dichlorobenzene 1,4-dichlorobenzene

REVIEW OF BENZENE PROPERTIES

BENZENE RESONANCE KEKULE STRUCTURES Resonance Energy = 36 Kcal / mole All bonds are equivalent The ring is symmetric. Bond lengths are between a single and a double bond. Very Stable Less reactive than other groupings of atoms.

H H HH H H All 2p orbitals overlap equally.

cyclohexatriene (hypothetical) benzene cyclohexene cyclohexane RESONANCE ENERGY 36 kcal/mol kcal/mol (calculated) kcal/mol kcal/mol BENZENE - DETERMINATION OF RESONANCE ENERGY

REACTIVITY

The “Double Bonds” in a Benzene Ring Do Not React Like Others AlkeneBenzene ++ no reaction ++ no reaction + + no reaction + + no reaction

+ + Stronger base Weaker base Readily donates electrons to an electrophile. Donation of electrons would interrupt ring resonance (36 kcal / mole). A strong electrophile is required - and often a catalyst. Benzene is a Weak Base and Poor Nucleophile alkene benzene

Benzene requires a strong electrophile and a catalyst …..and then it undergoes substitution reactions, not addition. + + Benzene Reactivity substitution catalyst + compare: addition no catalyst

Some Substitution Reactions of Benzene Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation Nitration Sulfonation

MECHANISM All of the reactions follow the same pattern of mechanism. The reagents combine to form a strong electrophile E +,and its partner (:X ), which react as follows: + + :X intermediate benzenium ion* (+) ELECTROPHILIC AROMATIC SUBSTITUTION + HX slow resonance structures are shown by the (+) symbols * also called a benzenonium ion restores ring resonance

ENERGY PROFILE FOR AROMATIC SUBSTITUTION + + Ea H + benzenium intermediate (+) Transition state 1 Transition state 2 STEP 1STEP 2 slowfast activation energy intermediate

HALOGENATION

Formation of the Chloronium Ion Complex ::: : : : : : : : : : : : : : : :: :..   Al Cl chloronium ion complex sp 2..

Chlorination of Benzene HAlCl 4 HCl + AlCl 3 chloronium ion complex [] + benzenium ion Cl 2 + AlCl 3

FRIEDEL-CRAFTS REACTIONS

FRIEDEL-CRAFTS ALKYLATION

:: : : : : : : : : : :: : :: :..  + - .. carbocation Formation of a Carbocation Complex Other aliphatic R-Cl may be used

Friedel-Crafts Alkylation + - [] + CH 3 Cl + AlCl 3 + HAlCl 4 HCl + AlCl 3 -

REARRANGEMENTS ARE COMMON IN FRIEDEL-CRAFTS ALKYLATION AlCl 3 carbocation rearrangement + AlCl 3

FRIEDEL-CRAFTS ACYLATION

:: : : : : : : : : : :: : :: :..  + - .. acylium ion Formation of an Acylonium Complex Other acid chlorides (RCOCl) may be used Rearrangements DO NOT occur (acylonium ion)

Friedel-Crafts Acylation + - [] + + AlCl 3 + HAlCl 4 HCl + AlCl 3 -

X doesn’t work - rearranges LINEAR CHAINS ARE MADE VIA ACYLATION (no rearrangement) AND REMOVAL OF C=O Clemmensen

NITRATION

Formation of Nitronium Ion.. H 2 SO 4 :: : : :: : : : nitronium ion +.. : : Powerful Electrophile Reacts with benzene.

+ + : : : : : : :: Nitration of Benzene HNO 3 H 2 SO 4

SULFONATION

Fuming Sulfuric Acid H 2 SO 4 SO 3. sulfur trioxide :.. : : : :

Sulfonation of Benzene + - H 2 SO 4 SO 3. + H 2 SO 4 can be reversed in boiling water or steam (acidic) H3O+H3O+ 

REMOVAL OF THE SULFONATE GROUP excess H 2 O heat or steam

Benzoic Acid Syntheses

KMnO 4 CH 3 Cl AlCl 3 Br 2 AlBr 3 1 Li 2 CO 2 3 H 3 O + CH 3 OH Synthesis of Benzoic Acids and Benzoate Esters

AROMATIC ? WHERE DID THE TERM ORIGINALLY COME FROM ?

A LOT OF NICE-SMELLING COMPOUNDS A LOT OF NICE-SMELLING COMPOUNDS (SPICES IN PARTICULAR) HAVE BENZENE RINGS Hence, compounds having benzene rings eventually came to be know as “AROMATIC COMPOUNDS. Today chemists have a different definition of “AROMATIC” which we will discuss later in the chapter. anisaldehyde (anise) cinnamaldehyde (cinnamon) thymol (thyme) eugenol (cloves) cuminaldehyde (cumin)

DIRECTIVITY AND DIRECTIVITY AND RING ACTIVATION / DEACTIVATION

Nitration of Anisole Reacts faster than benzene + orthopara = “ACTIVATED” The -OCH 3 group when it preexists on the ring gives only ortho and para products, and no meta. Substituents that cause this result are called o,p directors HNO 3 H 2 SO 4 and they usually activate the ring. anisole ACTIVATED RING

Nitration of Methyl Benzoate Reacts slower than benzene meta HNO 3 H 2 SO 4 = “DEACTIVATED” methyl benzoate The -COOMe group when it preexists on the ring gives only meta, and no ortho or para products. Substituents that cause this result are called m directors and they usually deactivate the ring. DEACTIVATED RING

Most ring substituents fall into one of these two categories: o,p - directorsm- directors activate the ringdeactivate the ring SUBSTITUENT CATEGORIES We will look at one of each kind in order to understand the difference…..

NITRATION OF ANISOLE

Nitration of Anisole actual products activated ring orthometapara ortho para +

ortho meta para : : EXTRA!

Energy Profiles meta ortho para NITRATION OF ANISOLE benzenium intermediate RECALL: HAMMOND POSTULATE EaEa benzenium intermediates have more resonance ortho-para director

doesn’t happen resonance would be lost restores aromatic ring resonance ADDITION REACTION ELIMINATION REACTION BENZENIUM IONS GIVE ELIMINATION INSTEAD OF ADDITION ( 36 Kcal / mole ) X

NITRATION OF METHYL BENZOATE

Nitration of Methyl Benzoate actual product deactivated ring orthometapara meta

ortho meta para     BAD!

ortho meta para Energy Profiles NITRATION OF METHYL BENZOATE some benzenium resonance structures have a bad situation meta director

DIRECTIVITY OF SINGLE GROUPS

ortho, para - Directing Groups Groups that donate electron density to the ring. : +I Substituent+R Substituent CH 3 - R- CH 3 -O- CH 3 -N- -NH 2 -O-H These groups also “activate” the ring, or make it more reactive. E+E+ The +R groups activate the ring more strongly than +I groups... increased reactivity PROFILE:

meta - Directing Groups Groups that withdraw electron density from the ring. These groups also “deactivate” the ring, or make it less reactive. E+E+ -I Substituent-R Substituent  -SO 3 H + decreased reactivity + - PROFILE:

Halides - o,p Directors / Deactivating E+E+ ::.. Halides represent a special case: They are o,p directors (+R effect ) They are deactivating ( -I effect ) Most other other substituents fall into one of these four categories: 1) +R / o,p / activating 2) +I / o,p / activating 3) -R / m / deactivating 4) -I / m / deactivating +R / -I / o,p / deactivating They are o,p directing groups that are deactivating -F -Cl -Br -I THE EXCEPTION

PREDICT ! o,pm m

DIRECTIVITY OF MULTIPLE GROUPS

GROUPS ACTING IN CONCERT m-director o,p director HNO 3 H 2 SO 4 major product very little formed steric crowding When groups direct to the same positions it is easy to predict the product.

GROUPS COMPETING o,p-directing groups win over m-directing groups HNO 3 H 2 SO 4 too crowded X +

HNO 3 H 2 SO 4 RESONANCE VERSUS INDUCTIVE EFFECT +R +I resonance effects are more important than inductive effects major product

SOME GENERAL RULES 1) Activating (o,p) groups (+R, +I) win over deactivating (m) groups (-R,-I). 2) Resonance groups (+R) win over inductive (+I) groups. 3) 1,2,3-Trisubstituted products rarely form due to excessive steric crowding. 4) With bulky directing groups, there will usually be more p-substitution than o-substitution. 5) The incoming group replaces a hydrogen, it will not usually displace a substituent already in place.

HOW CAN YOU MAKE... only, no para

BROMINE - WATER REAGENT PHENOLS AND ANILINES

.. ::: :: : BROMINE IN WATER + This reagent works only with highly-activated rings such as phenols, anisoles and anilines. bromonium ion etc

Br 2 H2OH2O All available positions are bromiated. Br 2 H2OH2O PHENOLS AND ANILINES REACT

AROMATICITY AROMATICITY THE HUCKEL RULE

QUESTION: Are all fully-conjugated, cyclic systems aromatic? AROMATICITY KNOWN AROMATIC ??? ?? 36 kcal/mole RE Do these other rings have the same kind of stability as benzene?

HUCKEL 4n+2 RULE.. Prediction: Compounds that have 4n+2 pi electrons in a cyclic array will be aromatic. AROMATICITY POLYCYCLIC AROMATIC COMPOUNDS benzenenaphthaleneanthracene n+2 series = 2, 6, 10, 14, 18, 22, 26, 30 …….. etc. The rule was derived by observation of

Aromatic Compounds Have Special Properties Aromatic compounds: 1) Must be cyclic and fully conjugated 2) Must have 4n+2  electrons in the system 3) Must have the entire system planar Characteristic Properties: 1) Special chemical stability 2) Give substitution reactions instead of addition 3) Show a ring currrent in the NMR 4) Will have no unpaired electrons in the  system molecular orbitals planar system

12  14  4(3)  4(4)  4(2)  20  SOME CYCLIC POLYENES AROMATIC ANNULENES [10]-annulene [12]-annulene [14]-annulene [16]-annulene [18]-annulene [20]-annulene BUT CANNOT BE PLANAR (see the hydrogens)

HETEROCYCLIC COMPOUNDS.. pyridinepyrrolefuranthiophene All have 6  electrons in a cyclic array. The unshared pairs are in the cyclic pi system (one pair in each case). These compounds have reactions similar to benzene, rather than to alkenes. They will give substitution reactions under conditions similar to those for benzene. pair not in  system

X Cl - NaOEt EtOH The anion forms readily. The cation does not form at all. 66 44 CYCLOPENTADIENYL ANION AND CATION AROMATIC ANTI-AROMATIC The methylene hydrogens are acidic. This compound does not dissolve in water.

X Cl - NaOEt EtOH 88 66 CYCLOHEPTATRIENYL ANION AND CATION ANTI-AROMATICAROMATIC This compound ionizes easily in water. The methylene hydrogens are not acidic. Doesn’t form easily. Dissolves in water.